The document summarizes the synthesis and evaluation of novel pyridazinone derivatives bearing benzenesulfonamide moieties for their anticancer activity. A series of 8 pyridazinone derivatives (2a-h) were synthesized and 5 (2a, 2b, 2d, 2g, 2h) were evaluated against human cancer cell lines. Compound 2h showed the best results, inhibiting the growth of 34/59 cell lines with GI50 values below 1 μM for several cancer types. Acute toxicity studies in mice found 2h to be well tolerated at 400 mg/kg. Compound 2h was selected for further evaluation based on its promising anticancer activity and favorable toxicity profile.
5 phytochemical analysis of bitter melon juice; antiproliferative and apopto...BIOLOGICAL FORUM
ABSTRACT: Osteosarcoma is one of the most common cancers among adolescents and young adults. Prognosis of osteosarcoma is particularly poor, suggesting critical needs for additional drugs to improve disease outcome. In this study, osteosarcoma cell SaOS-2 was used as an in vitro model to assess the effect of bitter melon (Momordica charantia) juice (BMJ) as an anticancer agent. Fruit juice of Momordica charantia was subjected to preliminary phytochemical analysis to identify various phytoconstituents present in them such as carbohydrates, starch, flavonoids, phenols, steroids, terpenoids, alkaloids, tanins and saponins. Cell viability (MTT) results revealed that 1 to 10% (v/v) of BMJ treatment significantly (p<0.05) reduced the proliferation of SaOS-2 cells in a dose dependent manner. Antiproliferative activity of BMJ was also coupled with morphological changes in the cells with the significant induction of apoptosis as quantified by DAPI stain. Reactive oxygen species (ROS) generation was also significantly induced by BMJ treatment. Furthermore, flow cytometric analysis revealed that BMJ induced cell cycle arrest in G2/M phase with the enhancement of apoptosis. The findings of this study suggest that BMJ modulates ROS generation and cell cycle arrest in G2/M phase of SaOS-2 cells which lead to inhibition of cell proliferation and induction of apoptosis of osteosarcoma. These findings suggest that BMJ could be a potential agent for osteosarcoma treatment and anticancer drug discovery.
Growth inhibitory effects of vitamin k2 (menaquinones mk4) on bladder carcin...NAAR Journal
Ubiad1 is a tumor suppressor gene ubiquitously expressed in normal
human tissues and its protein harbors a prenyltransferase functional
domain conserved throughout the evolution. The ability of human
UBIAD1 enzyme to synthesize menaquinone-4 (MK-4) rescues
mitochondrial dysfunction in Drosophila and effectively initiates
apoptosis in various types of tumors through a caspase-dependent
pathway. The objective is to study menaquinone-4-induced apoptosis
signaling pathway and to investigate its anti-tumor activity in human
prostate (PC-3, LNCaP) and bladder (T24, J82) tumor cell lines, an
approach that has not been undertaken yet. Cell viability of cancerous cells
pre-treated with MK-4 showed a significant decrease in dose- and timedependent manner. Moreover, flow cytometry detected apoptotic cells
after treatment with the vitamin. Taken together, these observations
suggest that MK-4 could inhibit cell growth by promoting apoptosis in
prostate and bladder carcinoma cells via different-mediated signal
pathways, making it a potential therapeutic molecule for the prevention
and the cure of cancers.
Novel 1,3,4-Thiadiazole Linked Amide Derivatives of Pteridone: Synthesis and ...Ratnakaram Venkata Nadh
Cancer is a second leading cause of death after heart attack, in developing as well as undeveloped
countries. It is caused by unregulated growth and metastasis of the abnormal cancer cells.
Cancer can be cured by radiation, immunotherapy and chemotherapy, among them; chemotherapy is a
good treatment for cancer, in which chemotherapeutic drug is used. The anticancer activity of newly
synthesized compounds (13a-j) was carried out on four different types of human cancer cell lines like
MCF-7 (breast), A549 (lung), Colo-205 (colon) and A2780 (ovarian) by the MTT method, and compared
to etoposide used as a positive control. Among them, compound 13g with electron-withdrawing
(3,5-dinitro) group, exhibited more promising activity in all cell lines (MCF-7 = 0.10±0.076 μM, A549
= 0.17±0.039 μM, Colo-205= 0.13±0.022 μM and A2780 = 0.87±0.027μM). This compound may act
as lead drug in cancer chemotherapy. In future, this compound can be examined for clinical studies.
Pharmacogenetics is the study of inherited genetic differences in drug metabolic pathways which can affect individual responses to drugs, both in terms of therapeutic effect as well as adverse effects. The term pharmacogenetics is often used interchangeably with the term pharmacogenomics which also investigates the role of acquired and inherited genetic differences in relation to drug response and drug behavior through a systematic examination of genes, gene products, and inter- and intra-individual variation in gene expression and function.
Curcumin Based Nanotherapy of Cancer A Reviewijtsrd
Cancer is the most prevalent disease not only in the United States but worldwide. The most representative polyphenol component extracted from the rhizomes of Curcuma long a known as turmeric is curcumin. The therapeutic benefits of curcumin have been demonstrated in multiple chronic diseases inflammation, arthritis, metabolic syndrome, liver disease, obesity, neurodegenerative diseases and, above all, in several cancers. Chemotherapy is a major form of treatment modality for various human diseases and disorders in both developing and developed countries. This intervention has been associated with a number of side effects and poor compliance. Therefore, in recent years, a significant effort has been put forward for finding a better treatment modality that uses natural compounds or extracts. Among many naturally occurring polyphenol compounds, curcumin is a highly safe yellow pigment molecule, widely used as a food coloring agent, and can be used to treat various pathological conditions. Rushikesh Mulay | Rishikesh Bachhav "Curcumin Based Nanotherapy of Cancer - A Review" Published in International Journal of Trend in Scientific Research and Development (ijtsrd), ISSN: 2456-6470, Volume-5 | Issue-6 , October 2021, URL: https://www.ijtsrd.com/papers/ijtsrd46376.pdf Paper URL : https://www.ijtsrd.com/pharmacy/analytical-chemistry/46376/curcumin-based-nanotherapy-of-cancer--a-review/rushikesh-mulay
Targeting PIM kinase to overcome drug resistance in NSCLC - Dr Kathy GatelyHannahMcCarthy31
Dr Kathy Gately is a Clinical Scientist at St James's Hospital and Clinical Senior Lecturer at Trinity College Dublin. Dr Gately's research interests are Drug Resistance Mechanisms in Non-Small Cell Lung Cancer, Liquid Biopsy and Organoid models.
Immunologic tumour models in NSCLC - Dr Catriona DowlingHannahMcCarthy31
Dr Dowling is a lecturer in biomedical sciences and is a lung cancer researcher at the University of Limerick. Dr Dowling's special research interests are immuno-metabolism and basic science in lung cancer.
Design, synthesis and anti-tumour activity of new pyrimidine-pyrrole appended...Ratnakaram Venkata Nadh
The new pyrimidine-pyrrole scaffolds (7a–7m) with substituted 1,2,3-traizole moiety were synthesized in good
to mild yields and subjected for anti-cancer activity against melanoma and breast cancer cell lines using MTT
assay. The compounds 7f and 7m exhibited highest anti-cancer activity against both the tested cell lines in in
vitro assay. The molecular docking analysis provided the insights of binding orientation of pyrimidine-pyrrole
nucleus of current ligands and their crucial interactions with Cys797 and other residues of the EGFR tyrosine
kinase active site. The interactions of triazole and its various substituted groups with EGFR tyrosine kinase have
been discussed
It is my journal club presentation on Synthesis, Docking Studies and Anticancer Activity of New Substituted Pyrimidine and Triazolopyrimidine Glycosides.
I sincerely thank the authors Wael A. El-Sayed, Ashraf M. Mohamed , Hemat S. Khalaf, Dina S. EL-Kady, May Al-Manawaty
Novel Hybrid Molecules of Isoxazole Chalcone Derivatives: Synthesis and Study...Ratnakaram Venkata Nadh
medicine due to their significant role in the treatment of different health problems.
Methods: We have synthesized new series of isoxazole-chalcone conjugates (14a-m) by the
Claisen-Schmidt condensation of suitable substituted acetophenones with isoxazole aldehydes (12a-d).
In vitro cytotoxic activity of the synthesized compounds was studied against four different selected
human cancer cell lines by using sulforhodamine B (SRB) method.
Results: The adopted scheme resulted in good yields of new series of isoxazole-chalcone
conjugates (14a-m). Potent cytotoxic activity was observed for compounds -14a, 14b, 14e, 14i, 14j
and 14k against prostate DU-145 cancer cell line.
Conclusion: The observed potent cytotoxic activities were due to the presence of 3,4,5-
trimethoxyphenyl group.
5 phytochemical analysis of bitter melon juice; antiproliferative and apopto...BIOLOGICAL FORUM
ABSTRACT: Osteosarcoma is one of the most common cancers among adolescents and young adults. Prognosis of osteosarcoma is particularly poor, suggesting critical needs for additional drugs to improve disease outcome. In this study, osteosarcoma cell SaOS-2 was used as an in vitro model to assess the effect of bitter melon (Momordica charantia) juice (BMJ) as an anticancer agent. Fruit juice of Momordica charantia was subjected to preliminary phytochemical analysis to identify various phytoconstituents present in them such as carbohydrates, starch, flavonoids, phenols, steroids, terpenoids, alkaloids, tanins and saponins. Cell viability (MTT) results revealed that 1 to 10% (v/v) of BMJ treatment significantly (p<0.05) reduced the proliferation of SaOS-2 cells in a dose dependent manner. Antiproliferative activity of BMJ was also coupled with morphological changes in the cells with the significant induction of apoptosis as quantified by DAPI stain. Reactive oxygen species (ROS) generation was also significantly induced by BMJ treatment. Furthermore, flow cytometric analysis revealed that BMJ induced cell cycle arrest in G2/M phase with the enhancement of apoptosis. The findings of this study suggest that BMJ modulates ROS generation and cell cycle arrest in G2/M phase of SaOS-2 cells which lead to inhibition of cell proliferation and induction of apoptosis of osteosarcoma. These findings suggest that BMJ could be a potential agent for osteosarcoma treatment and anticancer drug discovery.
Growth inhibitory effects of vitamin k2 (menaquinones mk4) on bladder carcin...NAAR Journal
Ubiad1 is a tumor suppressor gene ubiquitously expressed in normal
human tissues and its protein harbors a prenyltransferase functional
domain conserved throughout the evolution. The ability of human
UBIAD1 enzyme to synthesize menaquinone-4 (MK-4) rescues
mitochondrial dysfunction in Drosophila and effectively initiates
apoptosis in various types of tumors through a caspase-dependent
pathway. The objective is to study menaquinone-4-induced apoptosis
signaling pathway and to investigate its anti-tumor activity in human
prostate (PC-3, LNCaP) and bladder (T24, J82) tumor cell lines, an
approach that has not been undertaken yet. Cell viability of cancerous cells
pre-treated with MK-4 showed a significant decrease in dose- and timedependent manner. Moreover, flow cytometry detected apoptotic cells
after treatment with the vitamin. Taken together, these observations
suggest that MK-4 could inhibit cell growth by promoting apoptosis in
prostate and bladder carcinoma cells via different-mediated signal
pathways, making it a potential therapeutic molecule for the prevention
and the cure of cancers.
Novel 1,3,4-Thiadiazole Linked Amide Derivatives of Pteridone: Synthesis and ...Ratnakaram Venkata Nadh
Cancer is a second leading cause of death after heart attack, in developing as well as undeveloped
countries. It is caused by unregulated growth and metastasis of the abnormal cancer cells.
Cancer can be cured by radiation, immunotherapy and chemotherapy, among them; chemotherapy is a
good treatment for cancer, in which chemotherapeutic drug is used. The anticancer activity of newly
synthesized compounds (13a-j) was carried out on four different types of human cancer cell lines like
MCF-7 (breast), A549 (lung), Colo-205 (colon) and A2780 (ovarian) by the MTT method, and compared
to etoposide used as a positive control. Among them, compound 13g with electron-withdrawing
(3,5-dinitro) group, exhibited more promising activity in all cell lines (MCF-7 = 0.10±0.076 μM, A549
= 0.17±0.039 μM, Colo-205= 0.13±0.022 μM and A2780 = 0.87±0.027μM). This compound may act
as lead drug in cancer chemotherapy. In future, this compound can be examined for clinical studies.
Pharmacogenetics is the study of inherited genetic differences in drug metabolic pathways which can affect individual responses to drugs, both in terms of therapeutic effect as well as adverse effects. The term pharmacogenetics is often used interchangeably with the term pharmacogenomics which also investigates the role of acquired and inherited genetic differences in relation to drug response and drug behavior through a systematic examination of genes, gene products, and inter- and intra-individual variation in gene expression and function.
Curcumin Based Nanotherapy of Cancer A Reviewijtsrd
Cancer is the most prevalent disease not only in the United States but worldwide. The most representative polyphenol component extracted from the rhizomes of Curcuma long a known as turmeric is curcumin. The therapeutic benefits of curcumin have been demonstrated in multiple chronic diseases inflammation, arthritis, metabolic syndrome, liver disease, obesity, neurodegenerative diseases and, above all, in several cancers. Chemotherapy is a major form of treatment modality for various human diseases and disorders in both developing and developed countries. This intervention has been associated with a number of side effects and poor compliance. Therefore, in recent years, a significant effort has been put forward for finding a better treatment modality that uses natural compounds or extracts. Among many naturally occurring polyphenol compounds, curcumin is a highly safe yellow pigment molecule, widely used as a food coloring agent, and can be used to treat various pathological conditions. Rushikesh Mulay | Rishikesh Bachhav "Curcumin Based Nanotherapy of Cancer - A Review" Published in International Journal of Trend in Scientific Research and Development (ijtsrd), ISSN: 2456-6470, Volume-5 | Issue-6 , October 2021, URL: https://www.ijtsrd.com/papers/ijtsrd46376.pdf Paper URL : https://www.ijtsrd.com/pharmacy/analytical-chemistry/46376/curcumin-based-nanotherapy-of-cancer--a-review/rushikesh-mulay
Targeting PIM kinase to overcome drug resistance in NSCLC - Dr Kathy GatelyHannahMcCarthy31
Dr Kathy Gately is a Clinical Scientist at St James's Hospital and Clinical Senior Lecturer at Trinity College Dublin. Dr Gately's research interests are Drug Resistance Mechanisms in Non-Small Cell Lung Cancer, Liquid Biopsy and Organoid models.
Immunologic tumour models in NSCLC - Dr Catriona DowlingHannahMcCarthy31
Dr Dowling is a lecturer in biomedical sciences and is a lung cancer researcher at the University of Limerick. Dr Dowling's special research interests are immuno-metabolism and basic science in lung cancer.
Design, synthesis and anti-tumour activity of new pyrimidine-pyrrole appended...Ratnakaram Venkata Nadh
The new pyrimidine-pyrrole scaffolds (7a–7m) with substituted 1,2,3-traizole moiety were synthesized in good
to mild yields and subjected for anti-cancer activity against melanoma and breast cancer cell lines using MTT
assay. The compounds 7f and 7m exhibited highest anti-cancer activity against both the tested cell lines in in
vitro assay. The molecular docking analysis provided the insights of binding orientation of pyrimidine-pyrrole
nucleus of current ligands and their crucial interactions with Cys797 and other residues of the EGFR tyrosine
kinase active site. The interactions of triazole and its various substituted groups with EGFR tyrosine kinase have
been discussed
It is my journal club presentation on Synthesis, Docking Studies and Anticancer Activity of New Substituted Pyrimidine and Triazolopyrimidine Glycosides.
I sincerely thank the authors Wael A. El-Sayed, Ashraf M. Mohamed , Hemat S. Khalaf, Dina S. EL-Kady, May Al-Manawaty
Novel Hybrid Molecules of Isoxazole Chalcone Derivatives: Synthesis and Study...Ratnakaram Venkata Nadh
medicine due to their significant role in the treatment of different health problems.
Methods: We have synthesized new series of isoxazole-chalcone conjugates (14a-m) by the
Claisen-Schmidt condensation of suitable substituted acetophenones with isoxazole aldehydes (12a-d).
In vitro cytotoxic activity of the synthesized compounds was studied against four different selected
human cancer cell lines by using sulforhodamine B (SRB) method.
Results: The adopted scheme resulted in good yields of new series of isoxazole-chalcone
conjugates (14a-m). Potent cytotoxic activity was observed for compounds -14a, 14b, 14e, 14i, 14j
and 14k against prostate DU-145 cancer cell line.
Conclusion: The observed potent cytotoxic activities were due to the presence of 3,4,5-
trimethoxyphenyl group.
Background: Nowadays, hybrid drugs have gained a significant role in the treatment of different
health problems. Most of the hybrid molecules with different heterocyclic moieties were proved
to be potent anti-tumor agents in cancer chemotherapy. Hence, the present study is aimed at the evaluation
of in vitro anticancer activity of novel hybrid molecules (pyrazolyl benzoxazole conjugates) and to
investigate their anticancer activity by molecular docking studies.
Methods: Designed, synthesized and characterized the novel pyrazolyl benzoxazole conjugates.
Anticancer activity of these compounds was determined by SRB assay. Then molecular docking studies
were carried out against proto-oncogene tyrosine-protein kinase (ATP-Src, PDB: 2BDF), a putative
target for cancer.
Results: All the synthesized compound derivatives were evaluated against MCF-7, KB, Hop62 and
A549 cancer cell lines. Compounds 9b and 9c exhibited excellent anticancer activities with GI50 values
of <0.1 μM against MCF-7 and A549 cell lines. Compound 9e exhibited good antitumor activity on
MCF-7 and A-549 with GI50 values of 0.12 μM and 0.19 μM respectively. Compound 9g showed better
anticancer activity on A-549 cancer cell line with GI50 value of 0.34 μM.
Conclusion: The two-hybrid molecules 9b and 9c are found to be comparably potent with the standard
drug doxorubicin and may act as drug lead compounds in medicinal chemistry aspect. The present
docking investigation proved that having benzoxazole of compound 9c at benzofuran of reference
compound N-acetyl pyrazoline derivative might be valid for contributing to anti-cancer activity.
Abstract: Background: Nowadays, hybrid drugs have gained a significant role in the treatment of different
health problems. Most of the hybrid molecules with different heterocyclic moieties were proved
to be potent anti-tumor agents in cancer chemotherapy. Hence, the present study is aimed at the evaluation
of in vitro anticancer activity of novel hybrid molecules (pyrazolyl benzoxazole conjugates) and to
investigate their anticancer activity by molecular docking studies.
Methods: Designed, synthesized and characterized the novel pyrazolyl benzoxazole conjugates.
Anticancer activity of these compounds was determined by SRB assay. Then molecular docking studies
were carried out against proto-oncogene tyrosine-protein kinase (ATP-Src, PDB: 2BDF), a putative
target for cancer.
Results: All the synthesized compound derivatives were evaluated against MCF-7, KB, Hop62 and
A549 cancer cell lines. Compounds 9b and 9c exhibited excellent anticancer activities with GI50 values
of <0.1 μM against MCF-7 and A549 cell lines. Compound 9e exhibited good antitumor activity on
MCF-7 and A-549 with GI50 values of 0.12 μM and 0.19 μM respectively. Compound 9g showed better
anticancer activity on A-549 cancer cell line with GI50 value of 0.34 μM.
Conclusion: The two-hybrid molecules 9b and 9c are found to be comparably potent with the standard
drug doxorubicin and may act as drug lead compounds in medicinal chemistry aspect. The present
docking investigation proved that having benzoxazole of compound 9c at benzofuran of reference
compound N-acetyl pyrazoline derivative might be valid for contributing to anti-cancer activity
Abnormal expression of Pygopus 2 correlates with a malignant phenotype in hum...Enrique Moreno Gonzalez
Pygopus 2 (Pygo2) is a Pygo family member and an important component of the Wnt signaling transcriptional complex. Despite this data, no clinical studies investigating Pygo2 expression in lung cancer have yet been reported.
Design, synthesis and anti-tumour activity of new pyrimidine-pyrrole appended...Ratnakaram Venkata Nadh
The new pyrimidine-pyrrole scaffolds (7a–7m) with substituted 1,2,3-traizole moiety were synthesized in good
to mild yields and subjected for anti-cancer activity against melanoma and breast cancer cell lines using MTT
assay. The compounds 7f and 7m exhibited highest anti-cancer activity against both the tested cell lines in in
vitro assay. The molecular docking analysis provided the insights of binding orientation of pyrimidine-pyrrole
nucleus of current ligands and their crucial interactions with Cys797 and other residues of the EGFR tyrosine
kinase active site. The interactions of triazole and its various substituted groups with EGFR tyrosine kinase have
been discussed
In-vitro biological activities of the free new H4L ( indole-7-thiocarbohydrazone) ligand and its Ni(II), Pd(II) , Pt(II),
Cu(II), Ag(I), Zn(II) and Cd(II) complexes are screened against two cancerous cell lines, that revealed significant
activity only for [Cu2Cl2(H4L)2(PPh3)2] after 72 h treatment by the highest tested concentrations. The Copper(I)
complex was characterized by X-ray Crystallography and the NMR spectra, whereas it has been confirmed to have
momentous cytotoxicity against ovarian, breast cancerous cell lines (Caov-3, MCF-7). The apoptosis-inducing
properties of the Cu(I) complex have been investigated through fluorescence microscopy visualization, DNA
fragmentation analysis and propidium iodide flow cytometry.
Anticancer Activity of New Di-Nuclear Copper (I) ComplexTaghreed Al-Noor
In-vitro biological activities of the free new H4L ( indole-7-thiocarbohydrazone) ligand and its Ni(II), Pd(II) , Pt(II),
Cu(II), Ag(I), Zn(II) and Cd(II) complexes are screened against two cancerous cell lines, that revealed significant
activity only for [Cu2Cl2(H4L)2(PPh3)2] after 72 h treatment by the highest tested concentrations. The Copper(I)
complex was characterized by X-ray Crystallography and the NMR spectra, whereas it has been confirmed to have
momentous cytotoxicity against ovarian, breast cancerous cell lines (Caov-3, MCF-7). The apoptosis-inducing
properties of the Cu(I) complex have been investigated through fluorescence microscopy visualization, DNA
fragmentation analysis and propidium iodide flow cytometry.
Low expression of N-myc downstream-regulated gene 2 in oesophageal squamous c...Enrique Moreno Gonzalez
It is currently unclear whether a correlation exists between N-myc downstream-regulated gene 2 (NDRG2) expression and oesophageal squamous cell carcinoma (ESCC). The aim of this study was to examine the underlying clinical significance of NDRG2 expression in ESCC patients and to investigate the effects of NDRG2 up-regulation on ESCC cell growth in vitro and in vivo.
HDAC4 and HDAC7 Promote Breast and Ovarian Cancer Cell Migration by Regulatin...CrimsonpublishersCancer
Breast and ovarian cancer have been remained as a highly malignant tumor among women, posing a serious threat to women health worldwide. In this study, we were aimed to investigate the underlying mechanism of breast and ovarian cancer cell migration. Wound healing assay showed that MDA-MB-231and C13* have higher migration potential compare with MCF-7 and OV2078 cells, as well as regulated epithelial-mesenchymal transition (EMT) marker. We found that HDAC4 and HADC7 mRNA are up regulated in MDA-MB-231 and C13* cells. Moreover, target HDAC4 and HDAC7 by TSA or shRNA block MDA-MB-231and C13* migration. These results reveal a new link between HDACs and EMT in the regulation of breast and ovarian cancer migration.
Slide 1: Title Slide
Extrachromosomal Inheritance
Slide 2: Introduction to Extrachromosomal Inheritance
Definition: Extrachromosomal inheritance refers to the transmission of genetic material that is not found within the nucleus.
Key Components: Involves genes located in mitochondria, chloroplasts, and plasmids.
Slide 3: Mitochondrial Inheritance
Mitochondria: Organelles responsible for energy production.
Mitochondrial DNA (mtDNA): Circular DNA molecule found in mitochondria.
Inheritance Pattern: Maternally inherited, meaning it is passed from mothers to all their offspring.
Diseases: Examples include Leber’s hereditary optic neuropathy (LHON) and mitochondrial myopathy.
Slide 4: Chloroplast Inheritance
Chloroplasts: Organelles responsible for photosynthesis in plants.
Chloroplast DNA (cpDNA): Circular DNA molecule found in chloroplasts.
Inheritance Pattern: Often maternally inherited in most plants, but can vary in some species.
Examples: Variegation in plants, where leaf color patterns are determined by chloroplast DNA.
Slide 5: Plasmid Inheritance
Plasmids: Small, circular DNA molecules found in bacteria and some eukaryotes.
Features: Can carry antibiotic resistance genes and can be transferred between cells through processes like conjugation.
Significance: Important in biotechnology for gene cloning and genetic engineering.
Slide 6: Mechanisms of Extrachromosomal Inheritance
Non-Mendelian Patterns: Do not follow Mendel’s laws of inheritance.
Cytoplasmic Segregation: During cell division, organelles like mitochondria and chloroplasts are randomly distributed to daughter cells.
Heteroplasmy: Presence of more than one type of organellar genome within a cell, leading to variation in expression.
Slide 7: Examples of Extrachromosomal Inheritance
Four O’clock Plant (Mirabilis jalapa): Shows variegated leaves due to different cpDNA in leaf cells.
Petite Mutants in Yeast: Result from mutations in mitochondrial DNA affecting respiration.
Slide 8: Importance of Extrachromosomal Inheritance
Evolution: Provides insight into the evolution of eukaryotic cells.
Medicine: Understanding mitochondrial inheritance helps in diagnosing and treating mitochondrial diseases.
Agriculture: Chloroplast inheritance can be used in plant breeding and genetic modification.
Slide 9: Recent Research and Advances
Gene Editing: Techniques like CRISPR-Cas9 are being used to edit mitochondrial and chloroplast DNA.
Therapies: Development of mitochondrial replacement therapy (MRT) for preventing mitochondrial diseases.
Slide 10: Conclusion
Summary: Extrachromosomal inheritance involves the transmission of genetic material outside the nucleus and plays a crucial role in genetics, medicine, and biotechnology.
Future Directions: Continued research and technological advancements hold promise for new treatments and applications.
Slide 11: Questions and Discussion
Invite Audience: Open the floor for any questions or further discussion on the topic.
Earliest Galaxies in the JADES Origins Field: Luminosity Function and Cosmic ...Sérgio Sacani
We characterize the earliest galaxy population in the JADES Origins Field (JOF), the deepest
imaging field observed with JWST. We make use of the ancillary Hubble optical images (5 filters
spanning 0.4−0.9µm) and novel JWST images with 14 filters spanning 0.8−5µm, including 7 mediumband filters, and reaching total exposure times of up to 46 hours per filter. We combine all our data
at > 2.3µm to construct an ultradeep image, reaching as deep as ≈ 31.4 AB mag in the stack and
30.3-31.0 AB mag (5σ, r = 0.1” circular aperture) in individual filters. We measure photometric
redshifts and use robust selection criteria to identify a sample of eight galaxy candidates at redshifts
z = 11.5 − 15. These objects show compact half-light radii of R1/2 ∼ 50 − 200pc, stellar masses of
M⋆ ∼ 107−108M⊙, and star-formation rates of SFR ∼ 0.1−1 M⊙ yr−1
. Our search finds no candidates
at 15 < z < 20, placing upper limits at these redshifts. We develop a forward modeling approach to
infer the properties of the evolving luminosity function without binning in redshift or luminosity that
marginalizes over the photometric redshift uncertainty of our candidate galaxies and incorporates the
impact of non-detections. We find a z = 12 luminosity function in good agreement with prior results,
and that the luminosity function normalization and UV luminosity density decline by a factor of ∼ 2.5
from z = 12 to z = 14. We discuss the possible implications of our results in the context of theoretical
models for evolution of the dark matter halo mass function.
Comparing Evolved Extractive Text Summary Scores of Bidirectional Encoder Rep...University of Maribor
Slides from:
11th International Conference on Electrical, Electronics and Computer Engineering (IcETRAN), Niš, 3-6 June 2024
Track: Artificial Intelligence
https://www.etran.rs/2024/en/home-english/
Multi-source connectivity as the driver of solar wind variability in the heli...Sérgio Sacani
The ambient solar wind that flls the heliosphere originates from multiple
sources in the solar corona and is highly structured. It is often described
as high-speed, relatively homogeneous, plasma streams from coronal
holes and slow-speed, highly variable, streams whose source regions are
under debate. A key goal of ESA/NASA’s Solar Orbiter mission is to identify
solar wind sources and understand what drives the complexity seen in the
heliosphere. By combining magnetic feld modelling and spectroscopic
techniques with high-resolution observations and measurements, we show
that the solar wind variability detected in situ by Solar Orbiter in March
2022 is driven by spatio-temporal changes in the magnetic connectivity to
multiple sources in the solar atmosphere. The magnetic feld footpoints
connected to the spacecraft moved from the boundaries of a coronal hole
to one active region (12961) and then across to another region (12957). This
is refected in the in situ measurements, which show the transition from fast
to highly Alfvénic then to slow solar wind that is disrupted by the arrival of
a coronal mass ejection. Our results describe solar wind variability at 0.5 au
but are applicable to near-Earth observatories.
Richard's aventures in two entangled wonderlandsRichard Gill
Since the loophole-free Bell experiments of 2020 and the Nobel prizes in physics of 2022, critics of Bell's work have retreated to the fortress of super-determinism. Now, super-determinism is a derogatory word - it just means "determinism". Palmer, Hance and Hossenfelder argue that quantum mechanics and determinism are not incompatible, using a sophisticated mathematical construction based on a subtle thinning of allowed states and measurements in quantum mechanics, such that what is left appears to make Bell's argument fail, without altering the empirical predictions of quantum mechanics. I think however that it is a smoke screen, and the slogan "lost in math" comes to my mind. I will discuss some other recent disproofs of Bell's theorem using the language of causality based on causal graphs. Causal thinking is also central to law and justice. I will mention surprising connections to my work on serial killer nurse cases, in particular the Dutch case of Lucia de Berk and the current UK case of Lucy Letby.
Cancer cell metabolism: special Reference to Lactate PathwayAADYARAJPANDEY1
Normal Cell Metabolism:
Cellular respiration describes the series of steps that cells use to break down sugar and other chemicals to get the energy we need to function.
Energy is stored in the bonds of glucose and when glucose is broken down, much of that energy is released.
Cell utilize energy in the form of ATP.
The first step of respiration is called glycolysis. In a series of steps, glycolysis breaks glucose into two smaller molecules - a chemical called pyruvate. A small amount of ATP is formed during this process.
Most healthy cells continue the breakdown in a second process, called the Kreb's cycle. The Kreb's cycle allows cells to “burn” the pyruvates made in glycolysis to get more ATP.
The last step in the breakdown of glucose is called oxidative phosphorylation (Ox-Phos).
It takes place in specialized cell structures called mitochondria. This process produces a large amount of ATP. Importantly, cells need oxygen to complete oxidative phosphorylation.
If a cell completes only glycolysis, only 2 molecules of ATP are made per glucose. However, if the cell completes the entire respiration process (glycolysis - Kreb's - oxidative phosphorylation), about 36 molecules of ATP are created, giving it much more energy to use.
IN CANCER CELL:
Unlike healthy cells that "burn" the entire molecule of sugar to capture a large amount of energy as ATP, cancer cells are wasteful.
Cancer cells only partially break down sugar molecules. They overuse the first step of respiration, glycolysis. They frequently do not complete the second step, oxidative phosphorylation.
This results in only 2 molecules of ATP per each glucose molecule instead of the 36 or so ATPs healthy cells gain. As a result, cancer cells need to use a lot more sugar molecules to get enough energy to survive.
Unlike healthy cells that "burn" the entire molecule of sugar to capture a large amount of energy as ATP, cancer cells are wasteful.
Cancer cells only partially break down sugar molecules. They overuse the first step of respiration, glycolysis. They frequently do not complete the second step, oxidative phosphorylation.
This results in only 2 molecules of ATP per each glucose molecule instead of the 36 or so ATPs healthy cells gain. As a result, cancer cells need to use a lot more sugar molecules to get enough energy to survive.
introduction to WARBERG PHENOMENA:
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1. Original article
Synthesis and evaluation of anticancer activity of some novel
6-aryl-2-(p-sulfamylphenyl)-pyridazin-3(2H)-ones
I.G. Rathish a
, Kalim Javed a,*, Shamim Ahmad a
, Sameena Bano a
, M.S. Alam a
, Mymoona Akhter b
,
K.K. Pillai c
, Syed Ovais a
, Mohammed Samim a
a
Department of Chemistry, Faculty of Science, Jamia Hamdard (Hamdard University), New Delhi 110 062, India
b
Drug Design and Medicinal Chemistry Lab, Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Jamia Hamdard (Hamdard University), New Delhi, India
c
Department of Pharmacology, Faculty of Science, Jamia Hamdard (Hamdard University), New Delhi, India
a r t i c l e i n f o
Article history:
Received 22 July 2011
Received in revised form
14 December 2011
Accepted 12 January 2012
Available online 20 January 2012
Keywords:
Pyridazinones
Benzenesulfonamides
Sulfonamides
Anticancer
Antiproliferative activity
a b s r a c t
A series of novel pyridazinone derivatives bearing benzenesulfonamide moiety (2aeh) has been
synthesized by the condensation of appropriate aroylacrylic acid and 4-hydrazinobenzenesulfonamide
hydrochloride in ethanol. Five derivatives (2a, 2b, 2d, 2g and 2h) were evaluated for their anticancer
activity toward human cancer cell lines by the National Cancer Institute. The 2h showed remarkable
activity against SR (leukemia) and NCI-H522 (non-small cell lung) with a GI50 value of less than 0.1 mM. It
also displayed good activity against leukemia (CCRF-CEM, HL-60 (TB), K-562, MOLT-4, RPMI-8226), non-
small cell lung cancer (NCI-H460), colon (HCT-116, HCT-15, HT29, KMI2, SW-620), CNS (SF-295), mela-
noma (MALME-3M, M14, MDA-MB-435 SK-MEL-5), ovarian (OVCAR-3, NCI/ADR-RES) and breast (MCF7)
cancer cell lines with a GI50 less than 1.0 mM. The acute toxicity study of 2h indicated that it is well
tolerated intra-peritoneally (400 mg/kg) by athymic nude mice. The 2h may possibly be used as lead
compound for developing new anticancer agents.
Ó 2012 Elsevier Masson SAS. All rights reserved.
1. Introduction
Among all diseases that affect humanity, cancer ranks high as
a major killer [1,2]. Although major advances have been made in the
chemotherapeutic management of some patients, the continued
commitment to the arduous task of discovering new anticancer
agents remains critically important. A large number of structurally
novel sulfonamide derivatives have recently been reported to show
substantial antitumor activity, both in vitro and/or in vivo.
Although they have a common chemical motif of aromatic/
heterocyclic sulfonamide, there are a variety of mechanisms of their
antitumor action, most of them poorly understood at this moment.
It is believed that carbonic anhydrase inhibition, cell cycle arrest in
the G1 phase, disruption of microtubule assembly, functional
suppression of the transcriptional activator NF-Y, and angiogenesis
(matrix metalloproteinase, MMP) inhibition may be among such
relevant mechanisms of these anticancer compounds. Some of
these derivatives are currently being evaluated in clinical trials, and
there is much optimism that they may lead to novel alternative
anticancer drugs, devoid of the side effects of the presently avail-
able pharmacological agents [3e5].
Pyridazinone derivatives have been reported to exhibit a wide
range of pharmacological activities such as antidepressant [6],
antihypertensive [7,8], antithrombotic [9], anticonvulsant [10],
cardiotonic [11], antibacterial [12], diuretic [13], anti-HIV [14],
aldose reductase inhibitors [15], hepatoprotective agents [16] and
COX-2 inhibitors [17]. It has also been reported that pyridazinone
derivative have remarkable anticancer activity [18,19].
In continuation of an ongoing program aiming at finding new
structure leads with potential chemotherapeutic activities [20e22]
it was thought worthwhile to synthesize and investigate the anti-
tumor activity of some novel pyridazinone derivatives comprising
the benzenesulfonamide moiety (2aeh). The data of these
synthesized compounds were submitted to National Cancer Insti-
tute (NCI), USA for antiproliferative activity. As per the protocol of
NCI, only five representative compounds 2a, 2b, 2d, 2g and 2h were
selected and granted NSC codes Viz; NSC 749115, NSC 749114, NSC
747557, NSC 749116 and NSC 747558 respectively and screened at
NCI for antiproliferative activity at a single high dose (10À5
M) in
full 60 cell panel. Compound (2h) NSC 747558 exhibited the best
result at a single dose and was selected for further evaluation at five
dose level screening. It showed remarkable antiproliferative
activity at five dose level screening and was referred to Biological
* Corresponding author. Tel.: þ91 9873463272.
E-mail addresses: kjaved@jamiahamdard.ac.in, kjavedchem@yahoo.co.in
(K. Javed).
Contents lists available at SciVerse ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
0223-5234/$ e see front matter Ó 2012 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2012.01.026
European Journal of Medicinal Chemistry 49 (2012) 304e309
2. Evaluation Committee of NCI for advanced study. This paper pres-
ents the synthesis of novel compounds (2aeh) and in vitro anti-
cancer efficacy against human cancer cell lines of 2a, 2b, 2d, 2g and
2h compounds.
2. Results and discussion
2.1. Chemistry
The synthetic route used to synthesize title compounds (2aeh)
is outlined in Scheme 1. The b-aroylacrylic acids (1aeh) required for
the synthesis of pyridazinones were obtained by a Friedel Craft’s
acylation through reported methods [23,24]. The cyclization to
pyridazinone derivatives bearing a benzenesulfonamide moiety
was afforded by the condensation of appropriate aroylacrylic acid
and 4-hydrazinobenzenesulfonamide hydrochloride in ethanol in
9.1e16.2% yield. The purity of the compounds was checked by TLC.
The structures of 2aeh were determined on the basis of elemental
analysis and by various spectroscopic methods such as IR, 1
H NMR,
13
C NMR and MS. Elemental analysis (C, H, N & S) data were within
Æ0.4% of the theoretical values. Spectral data IR, 1
H NMR, 13
C NMR
and MS of compounds were found in full agreement with the
proposed structure. IR spectra showed prominent bands for NH2 at
3302e3299 cmÀ1
, and 3164e3158 cmÀ1
, for cyclic carbonyl at
1659e1651 cmÀ1
, for C]N at 1599e1579 cmÀ1
and for SO2N < at
1343e1336 cmÀ1
and 1166e1163 cmÀ1
. In 1
H NMR spectra the
aromatic protons were observed at expected ppms. The signal for
SO2NH2 was observed as two-proton singlet or merged with the
signals of aromatic protonsin aromatic region.
2.2. Pharmacology
2.2.1. In vitro anticancer activity
Primary in vitro one-dose (10À5
M) anticancer assay was per-
formed using full panel of about 60 human tumor cell lines in
accordancewiththeprotocolof theDrugEvaluation Branch, National
Cancer Institute (NCI), Bethesda, and described elsewhere [25e31].
The human tumor cell lines were derived from nine different cancer
types: Leukemia, melanoma, lung, colon, CNS, ovarian, renal, pros-
tate, and breast cancers. Out of the synthesized compounds (2aeh),
five compounds, namely 2a, 2b, 2d, 2g and 2h were selected by the
National Cancer Institute (NCI). The compounds 2a, 2b, 2d and 2g
displayed no sensitivity towards human tumor cell lines. The
compound 2h (NSC 747558) possessed considerable anti-
proliferative activity (Table S1, Supplementary data) and it was
selected for an advanced assay against a full panel (approximately 60
cell lines) at five concentrations at 10-fold dilution (100,10,1, 0.1 and
0.001 mM). A 48 h continuous drug exposure protocol was used and
sulforhodamine B (SRB) protein assay was used to estimate cell
growth. Details of this system and the information which is encoded
by the activity pattern over all cell lines have been published
[25e27]. The anticancer activity of tested compounds is given by
three parameters for each cell line: log GI50 value (GI50 ¼ molar
concentration of thecompound thatinhibits50%netcell growth), log
TGI value (TGI ¼ molar concentration of the compound leading to
totalinhibition)andlogLC50 value(LC50 ¼ molarconcentrationof the
compound leading to 50% net cell death). Furthermore, a mean graph
midpoint (MG_MID) is calculated for each of the mentioned
parameters, giving an averaged activity parameter over all cell lines.
For the calculation of the MG_MID, insensitive cell lines are included
with the highest concentration tested. Selectivity of the compound
withrespect to one or more cell lines of the screen is characterized by
a high deviation (Δ) of the particular cell line parameter compared to
the MG_MID value.
The 2h inhibited the growth of 34 cells of the tested 59 tumor cell
lines (log GI50 À7.05 to À6.65). It showed remarkable activity against
SR (leukemia) and NCI-H522 (non-small cell lung) with a GI50 value
of less than 0.1 mM. It also displayed good activity against leukemia
(CCRF-CEM, HL-60 (TB), K-562, MOLT-4, RPMI-8226), non-small cell
lung cancer (NCI-H460), colon (HCT-116, HCT-15, HT29, KMI2, SW-
620), CNS (SF-295), melanoma (MALME-3M, M14, MDA-MB-435
SK-MEL-5), ovarian (OVCAR-3, NCI/ADR-RES) and breast (MCF7)
cancer cell lines with a GI50 less than 1.0 mM (Table 1).
2.2.2. Acute toxicity determination
Animal toxicity experiment was performed on the 2h. To
determine maximum tolerated dose (MTD) this compound was
intraperitoneal (ip) administrated to athymic nude mice at the
doses of 100, 200 and 400 mg/kg. The highest dose resulted in no
body weight loss or lethality, indicating that 2h was well tolerated.
2.2.3. Hollow fiber assay
On the basis of these results, 2h was selected for a preliminary
in vivo testing. The hollow fiber assay, developed at the NCI, is
a screening tool for assessing the potential anticancer activity of
compounds against human tumor cells cultivated in hollow fibers
and implanted intra-peritoneally and subcutaneously in mice [28].
After treatment by ip route, fiber cultures were collected and the
viable cell mass was determined. A scoring system was developed
to simplify evaluation of the results. For this, a value of 2 was
assigned for each compound dose which results in a 50% or greater
reduction (%T/C 50) in viable cell mass. The intraperitoneal and
subcutaneous sample was scored separately. Compound with
a combined ip þ sc score !20, a sc score !8 or a net cell kill of one
or more cell lines is considered as active in this testing. The 2h
displayed no activity in this preliminary in vivo testing.
2a-h
1a-h
O
O O
Anhy. AlCl3
OH
O O
R3
R2
R1
SO2NH2
NHNH2.HCl
NN
O
SO2NH2
R3
R2
R1
Absolute ethyl
alcohol/reflux
R3
R2
R1
1 2
3
45
2" 6"
2'3'
4'
5'
6'
3'' 5''
(a) R1 = R2 = R3 = H (b) R1 = R2 = H, R3 = Chloro
(c) R1 = R2 = H, R3 = Methyl (d) R1 = R2 = H, R3 = Methoxy
(e) R1 = H, R2 = Methyl, R3 = Chloro (f) R1 = Methyl, R2 = H, R3 = Methyl
(g) R1 = R2 = H, R3 = Biphenyl (h) R1 = R2 = H, R3 = Ethyl
Scheme 1. Synthesis of 6-aryl-2-benzenesulfonamide-pyridazinones (2aeh).
I.G. Rathish et al. / European Journal of Medicinal Chemistry 49 (2012) 304e309 305
4. 3. Conclusion
Cyclocondensation of appropriate aroylacrylic acid and 4-
hydrazinobenzenesulfonamide hydrochloride yielded pyridazinone
derivatives bearing a benzenesulfonamide moiety (2aeh). The
structures proposed to the synthesized compounds are well sup-
ported by spectroscopic data and elemental analyses. One of these
derivatives (2h) had excellent in vitro anticancer activity and can be
used as lead compound for developing new anticancer agents.
4. Experimental
4.1. Chemistry
Melting points were determined by open capillary tubes and are
uncorrected. All the Fourier Transform Infra Red (FTIR) spectra were
recorded on a Bio-rad FTS-135 spectrophotometer using KBr
pellets; nmax values are given in cmÀ1
. 1
H NMR spectra were
recorded on a Bruker Spectrospin DPX 300-MHz spectrometer
using deuterated DMSO as solvent and tetramethyl silane (TMS) as
an internal standard. Chemical shifts are given in d (ppm) scale and
coupling constants (J values) are expressed in Hz. Mass spectra (MS)
were scanned by affecting FAB ionization JEOL-JMS-DX 303 system,
equipped with direct inlet probe system. The m/z values of the more
intense peaks are mentioned. Purity of the compounds was
checked on TLC plates (silica gel G) which were visualized by
exposing to iodine vapors. Elemental analysis was carried out on
CHNS Elementar (Vario EL III).
4.1.1. General procedure for the synthesis of 6-aryl-2-
benzenesulfonamide-pyridazinones (2aeh)
A mixture of appropriate b-aroylacrylic acid (1aeh) (0.001 mol)
and 4-hydrazinobenzenesulfonamide hydrochloride (0.001 mol) in
absolute ethanol (20e30 mL) was refluxed for 48 h. The solvent
ethyl alcohol was removed by distillation method. The solid residue
thus obtained was converted into fine powder, which was stirred
with 5% sodium bicarbonate solution (25 mL). It was filtered,
washed with 2% acetic acid and then with water. It was dried and
crystallized from methanol (2aec, 2eeh) or acetone (2d). The
purity of the compounds was checked on TLC plate (Silica gel G) in
the solvent system Toluene : Ethyl acetate : Formic acid (5 : 4 : 1).
The intermediates, b-aroylacrylic acids (1aeh) required for the
synthesis of pyridazinones were prepared through reported
procedures [23,24].
4.1.1.1. 6-Phenyl-2-benzenesulfonamidepyridazine-3(2H)-one (2a).
Shiny off white crystals (m.p. 290e291 C). Yield 42.7%. Rf ¼ 0.67. 1
H
NMR (DMSO-d6, d): 7.24 (1H, d, J ¼ 9.71 Hz, H-4), 7.53 (5H, m,
SO2NH2, H-30, H-40, H-50), 7.94 (6H, m, H-20, H-60 and N-phenyl
protons), 8.19 (1H, d, J ¼ 9.70 Hz, H-5). IR ymax (KBr): 3311 cmÀ1
and
3161 cmÀ1
(NH2), 1656 cmÀ1
(C]O), 1587 cmÀ1
(C]N), 1338 cmÀ1
and 1166 cmÀ1
(SO2N). FAB-MS (m/z): 327 [Mþ
]. 13
C NMR (75 MHz,
DMSO, d): 131.89 (C-5 pyridazinone), 134.48 (C-4 pyridazinone),
145.11 (C-6 pyridazinone), 159.07 (C-3 pyridazinone). Anal. Calcd for
C16H13N3O3S: C, 58.7; H, 4.00; N, 12.84; S, 9.80; Found: C, 58.5; H,
4.03; N, 13.02; S, 9.71.
4.1.1.2. 6-(4-Chlorophenyl)-2-benzenesulfonamidepyridazine-3(2H)-
one (2b). Shiny off white crystals (m.p. 282e283 C). Yield 60.3%.
Rf ¼ 0.68. 1
H NMR (DMSO-d6, d): 7.21 (1H, d, J ¼ 9.77 Hz, H-4), 7.32
(2H, d, J ¼ 7.81 Hz, H-30, H-50), 7.49 (2H, s, SO2NH2), 7.84 (2H, d,
J ¼ 7.86 Hz, H-20, H-60), 7.91 (2H, d, J ¼ 8.53 Hz, H-300, H-500) 7.97 (2H,
d, J ¼ 8.48 Hz, H-200, H-600), 8.15 (1H, d, J ¼ 9.79 Hz, H-5). IR ymax
(KBr): 3302 cmÀ1
and 3158 cmÀ1
(NH2), 1659 cmÀ1
(C]O),
1596 cmÀ1
(C]N), 1340 cmÀ1
and 1163 cmÀ1
(SO2N).FAB-MS (m/z):
361 [Mþ
], 362 [Mþ1], 363 [Mþ2], 364 [Mþ3]. 13
C NMR (75 MHz,
DMSO, d): 131.80 (C-5 pyridazinone), 133.35 (C-4 pyridazinone),
144.38 (C-6 pyridazinone), 159.00 (C-3 pyridazinone). Anal. Calcd
for C16H12ClN3O3S: C, 53.11; H, 3.34; N, 11.61; S, 8.86. Found: C,
53.02; H, 3.37; N, 11.52; S, 8.91.
4.1.1.3. 6-(4-Methylphenyl)-2-benzenesulfonamidepyridazine-3(2H)-
one (2c). Shiny off white crystals (m.p. 281e282 C).Yield 70.5%.
Rf ¼ 0.75. 1
H NMR (DMSO-d6, d): 8.15 (1H, d, J ¼ 9.82 Hz, H-5), 7.96
(2H, d, J ¼ 8.50 Hz, H-200, H-600), 7.91 (2H, d, J ¼ 8.68 Hz, H-300, H-500),
7.84 (2H, d, J ¼ 7.96 Hz, H-20, H-60), 7.50 (2H, s, SO2NH2), 7.32 (2H, d,
J ¼ 7.87 Hz, H-30, H-50), 7.21 (1H, d, J ¼ 9.78 Hz, H-4), 2.36 (3H, s,
CH3). IR ymax (KBr): 3310 cmÀ1
and 3160 cmÀ1
(NH2), 1655 cmÀ1
(C]O), 1584 cmÀ1
(C]N), 1337 cmÀ1
and 1165 cmÀ1
(SO2N). FAB-
MS (m/z): 341 [Mþ
]. 13
C NMR (75 MHz, DMSO, d): 21.32 (CH3 at
C-40), 131.70 (C-5 pyridazinone), 131.81 (C-4 pyridazinone), 145.09
(C-6 pyridazinone), 159.04 (C-3 pyridazinone). Anal. Calcd for
C17H15N3O3S: C, 59.81; H, 4.43; N, 12.31; S, 9.39. Found: C, 59.69; H,
4.37; N, 12.22; S, 9.31.
4.1.1.4. 6-(4-Methoxyphenyl)-2-benzenesulfonamidepyridazine-
3(2H)one (2d). Shiny off white crystals (m.p. 290e291 C).Yield
48.6%. Rf ¼ 0.62. 1
H NMR (DMSO-d6, d): 8.15 (1H, d, J ¼ 9.80 Hz,
H-5), 7.88e7.94 (6H, m, N-phenyl protons, H-20, H-60), 7.50 (2H, s,
SO2NH2), 7.19 (1H, d, J ¼ 9.78 Hz, H-4), 7.06 (2H, d, J ¼ 8.70 Hz, H-30,
Table 1 (continued )
Panel/Tumor
cell lines
Log GI50 (M) Log TGI (M) Log LC50 (M) Selectivity toward tumor
cell lines (d) for log GI50/log
TGI/log LC50 (M)b
GI50 (mM)
Prostate Cancer
DU-145 À4.86 À4.00 À4.00 e 13.8
Breast Cancer
MCF7 À6.21 À4.72 À4.00 GI50 0.53/TGI 0.30 0.615
MDA-MB-231/ATCC À4.92 À4.00 À4.00 e 12.1
HS 578T À5.99 À4.77 À4.00 GI50 0.31/TGI 0.35 1.03
BT-549 À6.12 À4.75 À4.07 GI50 0.44/TGI
0.33/LC50 0.6
0.756
T-47D À5.59 À4.00 À4.00 e 2.56
MDA-MB-468 À5.50 À4.00 À4.00 e 3.18
MG_MID L5.68 L4.42 L4.01
*The value in parenthesis represent the GI50 for the 5-FU (Fluorouracil) standard drug.
a
Data obtained from hte NCI’s in vitro disease-oriented human tumor cells.
b
The reported data represent the logarithmic difference between the parametric value referred to the most sensitive cell line and the same mean parameter, d is considered
low if 1, moderate 1 and 3, high if 3.
I.G. Rathish et al. / European Journal of Medicinal Chemistry 49 (2012) 304e309 307
5. H-50), 3.82 (3H, s, OCH3). IR ymax (KBr): 3317 cmÀ1
and 3294 cmÀ1
(NH2), 1657 cmÀ1
(C]O), 1599 cmÀ1
(C]N), 1334 cmÀ1
and
1161 cmÀ1
(SO2N), 1033 cmÀ1
(OCH3). FAB-MS (m/z): 357 [Mþ
]. 13
C
NMR (75 MHz, DMSO, d): 55.77 (OCH3 at C-40), 131.62 (C-5 pyr-
idazinone), 131.95 (C-4 pyridazinone), 144.92 (C-6 pyridazinone),
158.94 (C-3 pyridazinone). Anal. Calcd for C17H15N3O4S: C, 57.13; H,
4.23; N, 11.76; S, 8.97. Found: C 57.09; H, 4.31; N, 11.62; S, 8.89.
4.1.1.5. 6-(4-Chloro-3-methylphenyl)-2-benzenesulfonamidepyrida-
zine-3(2H)-one (2e). Shiny off white crystals (m.p. 289e290C).
Yield 57.8%. Rf ¼ 0.77. 1
H NMR (DMSO-d6, d): 8.19 (1H, d,
J ¼ 9.60 Hz, H-5), 7.81e7.98 (5H, m, N-phenyl protons and H-20), 7.80
(1H, d, J ¼ 8.33 Hz, H-60), 7.54 (3H, SO2NH2 and H-50), 7.25 (1H, d,
J ¼ 9.75 Hz, H-4), 2.40 (3H, s, CH3). IR ymax (KBr): 3302 cmÀ1
and
3164 cmÀ1
(NH2), 1651 cmÀ1
(C]O), 1584 cmÀ1
(C]N), 1343 cmÀ1
and 1164 cmÀ1
(SO2N). FAB-MS (m/z): 375 [Mþ
], 376 [Mþ1], 377
[Mþ2], 378 [Mþ3]. 13
C NMR (75 MHz, DMSO, d): 20.04 (CH3 at C-40),
132.40 (C-5 pyridazinone), 133.86 (C-4 pyridazinone), 154.35 (C-6
pyridazinone), 159.86 (C-3 pyridazinone). Anal. Calcd for
C17H14ClN3O3S: C, 54.33; H, 3.75; N, 11.18; S ¼ 8.53. Found: C, 54.19;
H, 3.61; N, 11.10; S, 8.41.
4.1.1.6. 6-(2,4-dimethylphenyl)-2-benzenesulfonamidepyridazine-
3(2H)-one (2f). Shiny off white crystals (m.p. 230e231 C). Yield
40.2%. Rf ¼ 0.73. 1
H NMR (DMSO-d6, d): 7.95 (2H, d, J ¼ 7.86 Hz, H-
200, H-600), 7.85 (2H, d, J ¼ 7.95 Hz, H-300, H-500), 7.76 (1H, d,
J ¼ 9.56 Hz, H-5), 7.49 (2H, s, SO2NH2), 7.38 (1H, d, J ¼ 9.56 Hz, H-
4), 7.14e7.15 (3H, m, H-30, H-50, H-60), 2.32 (3H, s, CH3), 2.34 (3H,
s, CH3). IR ymax (KBr): 3311 cmÀ1
and 3161 cmÀ1
(NH2), 1654 cmÀ1
(C]O), 1580 cmÀ1
(C]N), 1343 cmÀ1
and 1166 cmÀ1
(SO2N).FAB-
MS (m/z): 355 [Mþ
]. 13
C NMR (75 MHz, DMSO, d): 20.81 (CH3 at C-
20), 21.42 (CH3 at C-40), 133.46 (C-4 pyridazinone), 134.20 (C-5
pyridazinone), 151.40 (C-6 pyridazinone), 157.78 (C-3 pyr-
idazinone). Anal. Calcd for C18H17N3O3S: C, 60.83; H, 4.82; N,
11.82; S ¼ 9.02. Found: C, 60.75; H, 4.77; N, 11.75; S, 9.10.
4.1.1.7. 6-Biphenyl-2-benzenesulfonamidepyridazine-3(2H)-one (2g).
Shiny off white crystals (m.p. 272e273 C). Yield 45.7%. Rf ¼ 0.55.
1
H NMR (DMSO-d6, d): 7.33 (1H, d, J ¼ 9.72 Hz, H-4), 7.46e7.61 (5H,
m, SO2NH2, H-90, H-100, H-110), 7.82 (2H, d, J ¼ 7.83 Hz, H-80, H-120),
7.92 (2H, d, J ¼ 8.13 Hz, H-30, H-50), 8.02 (2H, d, J ¼ 8.66 Hz, H-300, H-
500), 8.06 (1H, d, J ¼ 8.47 Hz, H-200, H-600). 8.13 (2H, d, J ¼ 8.08 Hz, H-
20, H-60). IR ymax (KBr): 3311 cmÀ1
and 3161 cmÀ1
(NH2), 1654 cmÀ1
(C]O), 1579 cmÀ1
(C]N), 1336 cmÀ1
and 1165 cmÀ1
(SO2N). IR
ymax (KBr): 3311 cmÀ1
and 3161 cmÀ1
(NH2), 1654 cmÀ1
(C]O),
1579 cmÀ1
(C]N), 1336 cmÀ1
and 1165 cmÀ1
(SO2N). FAB-MS (m/
z): 403 [Mþ
], 404 [Mþ1]. 13
C NMR (75 MHz, DMSO, d): 131.80 (C-5
pyridazinone), 133.84 (C-4 pyridazinone), 153.80 (C-6 pyr-
idazinone), 159.4 (C-3 pyridazinone). Anal. Calcd for C22H17N3O3S:
C, 65.49; H, 4.25; N, 10.42; S ¼ 7.95. Found: C, 65.39; H, 4.17; N,
10.22; S, 7.80.
4.1.1.8. 6-(4-Ethylphenyl)-2-benzenesulfonamidepyridazine-3(2H)-
one (2h). Off white crystals (m.p. 275e276 C). Yield 72.8%. Rf ¼ 0.7.
1
H NMR (DMSO-d6, d): 8.15 (1H, d, J ¼ 9.76 Hz, H-5), 7.84e7.98 (6H,
m, N-phenyl protons, H-20, H-60), 7.50 (2H, s, SO2NH2), 7.34 (2H, d,
J ¼ 7.73 Hz, H-30, H-50), 7.21 (1H, d, J ¼ 9.76 Hz, H-4), 2.65 (2H, q,
CH2), 1.20 (3H, t, CH3). IR ymax (KBr): 3313 cmÀ1
and 3299 cmÀ1
(NH2), 1654 cmÀ1
(C]O), 1596 cmÀ1
(C]N), 1336 cmÀ1
and
1163 cmÀ1
(SO2N). FAB-MS (m/z): 355 [Mþ
], 356 [Mþ1]. 13
C NMR
(75 MHz, DMSO, d): 16.00 (CH3eCH2e at C-40), 21.42 (CH3eCH2e at
C-40), 131.86 (C-5 pyridazinone), 132.01 (C-4 pyridazinone), 146.19
(C-6 pyridazinone), 159.04 (C-3 pyridazinone). Anal. Calcd for
C18H17N3O3S: C, 60.83; H, 4.82; N, 11.82; S, 9.02. Found: C, 60.53; H,
4.77; N, 11.72; S, 8.92.
4.2. Pharmacology
4.2.1. In vitro anticancer activity
A total of 60 human tumor cell lines, derived from nine cancer
types (leukemia, lung, colon, brain, melanoma, ovarian, renal,
prostate and breast) formed the basis of this test. The tumor cells
were cultured in PMI1640 medium supplemented with 5% fetal calf
serum and 2 mM L-glutamine. The tumor cells are inoculated over
a series of standard 96-well microtrite plates in 100 mL of medium
[29,30]. Density of inoculum depends on the type of tumor cell and
from its growth characteristics [27]. These cells are then pre-
incubated on the microtrite plate for 24 h before adding the
compounds. These were tested in DMSO solution at five different
concentrations (10À4
, 10À5
, 10À6
, 10À7
and 10À8
M). After an incu-
bation of the chemical agent for 48 h with the tumor cell lines
a sulforhodamine B (SRB) protein assay was used to estimate cell
viability or growth. The cytotoxic effects are evaluated and the
assay results and doseeresponse parameters were calculated as
previously described [31].
4.2.2. Acute toxicity determination
The determination of maximum tolerated dose (MTD) is per-
formed in a way that conserves compound and minimizes the
number of animals sacrificed. Thus, a single mouse is given
a single injection (IP) of 400 mg/kg; a second mouse receives
a dose of.
200 mg/kg and a third mouse receive a single dose of 100 mg/kg.
The mice are observed for a period of 2 weeks. They are sacrificed if
they lose more than 20% of their body weight or if there are other
signs of significant toxicity. If all 3 mice must be sacrificed, the next
3 dose levels (50, 35 and 12.5 mg/kg) are tested in a similar manner.
This process is repeated until a tolerated dose is found. This dose is
then designated the MTD and is used to calculate the amount of
material administered to mice during antitumor testing. The mice
are allowed ad libitum feed and water. Injections are administered
IP. The compounds are solubilized in DMSO and dose volumes were
5 mL, 2.5 mL and 1.25 mL/g of body weight.
4.2.3. Hollow fiber assay
Human tumor cells were cultivated in polyvinylidene fluoride
hollow fibers, and a sample of each cell line was implanted into
each of two physiologic compartments (intraperitoneal and
subcutaneous) in mice. After treatment with 2h at two test doses
using a QD X 4 schedule, fiber cultures were collected and the viable
cell mass was determined using a formazan dye conversion assay. A
scoring system was developed to simplify evaluation of the results.
The cell lines used were: MDA-MB-231 and MDA-MB-435 (breast
cancer), NCI-H23 and NCI-H522 (lung cancer), OVCAR-3 and
OVCAR-5 (ovarian cancer), SF-295 and U-251 (CNS cancer), LOX
IMVI and UACC-62 (melanoma), COLO 205 and SW-620 (colon
cancer).
Acknowledgment
This work was supported by Grant No. 32-228/2006 (SR) from
the University Grants Commission, New Delhi, India. One of the
authors, I. G. Rathish is thankful to UGC for fellowship. We thank
the Antitumor Evaluation Branch of the National Cancer Institute
for performing biological evaluations.
Appendix. Supplementary material
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.ejmech.2012.01.026.
I.G. Rathish et al. / European Journal of Medicinal Chemistry 49 (2012) 304e309308
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