Combating drug resistance in anticancer therapy
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This document discusses strategies to combat drug resistance in anticancer therapy. It notes that continuous monitoring of patients and using a cocktail of drugs targeting multiple resistance pathways can help overcome resistance. Another strategy is intermittent "on and off" high and low dosing to interrupt growth of resistant cells. Blocking P-glycoprotein and depleting ATP can decrease drug resistance by inhibiting drug efflux. Using nanoparticles loaded with chemotherapy drugs and targeting molecules allows drugs to enter cancer cells. Genetic changes that increase drug-deactivating enzymes, membrane transporters, or DNA repair can also cause resistance.
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FTIR: -
Penicillin G molecule and its IR spectra in D2 O and in DMSO. Spectra are characterized by the presence of three intense bands.
β- lactam CO stretching observe at 1761 cm-1 in D2O and 1762 cm-1 in DMSO solution.
Amide group is observe at 1640 cm-1 in D2O and 1674 cm-1 in DMSO solution.
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MASS:-
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C13-NMR: -
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The slide is designed to impart knowledge about modern research techniques by enabling the molecular modification of a lead compound.
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Penicillin, one of the first and still one of the most widely used antibiotic agents, is derived from the penicillium mold. In 1928 Scottish bacteriologist alexander fleming in a contaminated green mold penicillium notatum. He isolated the mold, grew it in a fluid medium, and found that it produced a substance capable of killing many of the common bacteria that infect humans. Australian pathologist howard florey and British biochemist ernst Boris chain isolated and purified penicillin in the late 1930s, and by 1941 an injectable form of the drug was available for therapeutic use.
Penicillin's are beta lactam antibiotics and characterized by three fundamental structural requirements
The fused beta-lactam and thiazolidine ring structure.
free carboxylic acid group.
And one or more substituted acylamino side chain.
Penam nucleus: 7-oxo-l-thia-4-azabicyclo [3.2.0] heptane
Absolute configuration: 3-S, 5-R, 6-R.
Instrumental methods of characterization:
FTIR
MASS
C13-NMR
1H-NMR
FTIR: -
Penicillin G molecule and its IR spectra in D2 O and in DMSO. Spectra are characterized by the presence of three intense bands.
β- lactam CO stretching observe at 1761 cm-1 in D2O and 1762 cm-1 in DMSO solution.
Amide group is observe at 1640 cm-1 in D2O and 1674 cm-1 in DMSO solution.
Asymmetric stretching of carboxylate group is observe at 1601 cm-1 in D20 and 1615 cm-1 in DMSO solution.
A large red shift of amide , out of the frequency window, is observed upon proton exchange in DMSO.
Collision-Induced Dissociation (CID) technique
MASS:-
A high-resolution, hybrid tandem mass spectrometer was used to obtain CID spectra. The CID spectra were acquired by:
Mass selecting the precursor ions using the first mass spectrometer.
Injecting the ions into the first quadrupole (collision cell) where they undergo CID.
Mass-analyzing the fragment ions produced using the second quadrupole.
Argon was used as the collision gas, and the pressure in the collision cell was adjusted to attenuate the precursor ion intensity to 20-50% of the original intensity. The collision energy of the ions ranged from 160 to 180 eV. The mass spectra shown abundant fragmentations at m/z 160 and m/z 176 that were reported to arise from cleavage of the β-lactam ring.
protonated benzyl penicillin exhibits abundant fragment ions at m/z 160, m/z 176, m/z 217, m/z 128, and m/z 289. The most abundant CID fragment at m/z 160 and the molecular ion peak was observed at m/z 334.
C13-NMR: -
The four sp3 ring carbons give rise to resonances in the decreasing chemical shift order C-3, C-5, C-2 and C-6.
Chemical shift for C-2 is 64.9 ppm and the substituents attached with it are α-methyl 27.0 ppm and β-methyl 31.4 ppm. Chemical shift for C-3 is 73.6 ppm and 174.5 ppm for carboxylate functions (reflecting the smaller de-shielding influence of COOH over that of COO-). The chemic shift for C-5 is 67.2 ppm. The chemic shift for C-6 is 58.4 ppm.
The lactam group shows its chemical shift at 175.0 ppm
Amino group
Ugi Reaction
The document describes the Ugi reaction, a multi-component reaction where a ketone or aldehyde, amine, isocyanide, and carboxylic acid come together to form a bis-amide. It was first reported in 1959 by Ivar Karl Ugi. The reaction has high atom economy and yields, occurs rapidly at room temperature, and is uncatalyzed. It has applications in synthesizing chemical libraries and multiple compounds in one step, such as the HIV drug Crixivan. The mechanism involves imine formation, proton exchange, additions of the isocyanide and carboxylic acid, and a Mumm's rearrangement.
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- 1. Combating drug resistance in anticancer Therapy and Genetic principle of drug resistance Presented by, Maningcina Sephe 2021MPD2004 M.Pharm 1st semester Dept. of Pharmaceutical Chemistry RIPANS
- 2. INTRODUCTION Due to high complexity of evolution of tumor progressions, identifying the best strategy to overcome drug resistance will be very challenging. Combinational therapies are strongly preferred since tumors are almost always multi-clonal and genetically heterogeneous.
- 3. Strategy to combat drug resistance in anticancer therapy • 1. Continuous monitoring of patient • 2. on and off theraphy • 3. P-Glycoprotein inhibition • 4. Use of Nanoparticles
- 4. Continuous monitoring of patients and treatment • Continuous monitoring of Patients and treatment with a cocktail of chemotherapeutic drugs. Each targeting one or more proteins encoded by driver genes responsible for drug resistance pathway operating in cancer patients.
- 5. On and off therapy • The new treatment strategy “on or off” or “high dose followed by low dose” result in longer survival and delayed drug resistance. • This intermittent or adaptive dosing may interrupt the growth of drug depend resistant cells and allow the competition of sensitive and resistant cells.
- 6. Blockage of P- glycoprotein • P-Glycoprotein uses the energy in the form of ATP to pump drugs out of tumors. • By blocking this glycoprotein or depleting the ATP decrease the drug resistance
- 7. Use of Nanoparticles • The researcher made a “calcium ion nanogenerator” by loading calcium phosphate nanoparticles along with the chemotherapy drug and then coating them with molecules that would allow TCaNG to target and enter cancer cell.
- 8. Genetic principles of drug resistance • Generally drug resistance arises because of one or more of the following • Selection of cells that have increased expression of membrane glycoproteins, increased in levels of cytoplasmic thiols, increasing in deactivating or decrease in activating enzyme by changes in specific gene sequences and increase in DNA repair. • All of these mechanisms of resistance involve gene alterations.
- 9. • By increasing pools of cytoplasmic thiols, such as glutathione, the cell increases its ability to destroyed reactive electrophilic anticancer drugs. • More specifically gene encoding the family of glutathione S- transferases, which catalyze the reaction of glutathione with electrophilic compounds, may be altered so that enzymes are overproduced (gene prolification)
- 10. • Many drugs bind to DNA require enzymatic activation (prodrug). • The genes encoding these enzyme may be altered so that certain tumor cells no longer produce sufficient quantities of the activating enzymes to allow drugs to be effective. • Finally,once the DNA has been modified, a resistant cell could produce DNA repair enzymes, to excise the mutation in the DNA and repair polynucleotide strands.
- 11. References: • Drug Resistance in Cancer Therapy by Robert C.Young, Robert F.Ozols M.D..P.h.D • www.Wikipedia.com