This document discusses Vinca alkaloids, which are anti-cancer agents originally isolated from the Madagascar periwinkle plant. It covers the structure, mechanism of action, applications, and total synthesis of major Vinca alkaloids like vinblastine and vincristine. The document also summarizes emerging vinblastine-related compounds through modifications to the catharanthine and vindoline nuclei. Finally, it discusses drug targeting approaches for Vinca alkaloids like conjugating vinblastine to folic acid to selectively target cancer cells overexpressing folate receptors.

1. Vinca Alkaloids as anti-cancer agents
(Looking back and peering ahead)
Presented by
Mohd Abrar Khan
MC/2018/17
Department of Medicinal Chemistry
National Institute of Pharmaceutical Education And Research (NIPER), Hyderabad
Dept. of Pharmaceuticals, Ministry of Chemicals and Fertilizers, Govt. of India
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2. FLOW OF PRESENTATION
 Introduction
 Structure of Vinca Alkaloids
 Mechanism of Action
 Application of Vinca Alkaloids
 Total Synthesis
 Emerging Vinblastine related Compounds
 Drug Targetting Approaches
 Conclusion
 References
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3. Introduction
Cancer:
• A disease characterized by uncontrolled multiplication and
proliferation of abnormal forms of the body’s own cells.
• Second most common cause of death in Europe.
• According WHO in 2012, there were 14 million new cases
and this number is expected to increase up to 22 million
within the next two decades.
• Cancer is the second most common disease in India with a
mortality rate of 0.3 million deaths per year.
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4. Types of cancer
Bladder
Cancer
Breast
Cancer
Colorectal
Cancer
Prostate
Cancer
Leukemia Lung
Cancer
Pancreatic
Cancer
Thyroid
Cancer
4

5. Cancer Facts and Figures 2018. Atlanta, Ga: American Cancer Society, 2018.
Estimated New Cancer Cases in the US in 2018
5

6. Anti cancer drugs
Anticancer Drugs
Alkylating Agents Antimetabolites
Cytotoxic
Antibiotics
Plant Derivatives Hormones
Protein kinase
Inhibitors
Monoclonal
antibodies
• Nitrogen
mustards
• Nitrosoureas
• Platinum
Compounds
• Doxorubicin
• Epirubicin
• Daunorubicin
• Methotrexate
• Fluorouracil
• Mercaptopurine
• Megestrol
• Tamoxifen
• Axitinib
• lapatinib
Inhibition of
Growth factor
receptor
transduction
• Trastuzumab
• Rituximab
Inhibits cell
proliferation and
differentiation
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Taxanes
• Pacitaxel
• Docetaxel
Vinca Alkaloids
• Vinblastine
• Vincristine
Campothecins
• Irinotecan
• Topotecan
Podophyllotoxin
• Etoposide

7. VINCAALKALOIDS
VAs were originally isolated
• In 1950’s
• by Canadian scientists Robert Noble and Charles
Thomas Beer
• From the Madagascar periwinkle plant,
Catharanthus roseus of the Apocynaceae family.
• Eli Lilly found the cytotoxicity of extract in 1959.
VAs contain indole Alkaloids
• Vinblastine and Vincristine (0.0002%)
• That are the coupling products of the indole
alkaloids catharanthine and vindoline
Historical Review of Vinca Alkaloids. Acta Radiologica: Diagnosis. 1969; 8:7-12 7

8. STRUCTURE OF VINCAALKALOIDS
Vinca
Alkaloids
R1 R2 R3 R4 R5
Vinblastine -CH3 -CO2CH3 -OCOCH3 -CH2CH3 -CH2CH3
Vincristine -CHO -CO2CH3 -OCOCH3 -OH -CH2CH3
Vindesine -CH3 -CONH2 -OH -OH -CH2CH3
Vinorelbine -CH3 -CO2CH3 -OCOCH3 - -CH2CH3
Vinflunine -CH3 -CO2CH3 -OCOCH3 -H -CF2CH3
Catharanthine
Nucleus
Vindoline nucleus
Natural Alkaloids
Semisynthetic
Alkaloids
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9. Mechanism of Action
VAs binds to Tubulin
Inhibits polymerization
Preventing spindle formation
Causing arrest at Meta Phase
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10. MECHANISM OF ACTION
(At Low and High Conc.)
10
Pellegrini F, Budman DR. Review: tubulin function, actions of antitubulin drugs. Cancer Invest 2005;

11. CRYSTAL STRUCTURE
α Tubulin β Tubulin
Vinblastine
GTP
Crystal structure showing Vinblastine (VBL) bound to the interface of α/ β-tubulin dimers
(α-tubulin: light blue; β-tubulin: magenta; GTP: yellow) (PDB: 5J2T).
Gigant et al., 2005
Ravelli RBG, et al. Structural basis for the regulation of tubulin by vinblastine. Nature 2005; 435:519–522
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12. Vinca Alkaloids: Applications
Vinblastine
Leukemia
Hodgkin’s
lymphoma
Lung
Cancer
Breast
Cancer
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13. Vinca Alkaloids: Applications
Vincristine
B-cell
Lymphoma
Breast
cancer
Colorectal
cancer
Metastatic
carcinoma
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14. Vinca Alkaloids: Applications
Vindesine
Pediatric
Tumors
Esophageal
carcinoma
Renal
Carcinoma
Melanoma
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15. Vinca Alkaloids: Applications
Vinorelbine
Lung
cancer
Breast
cancer
Urothelial
cancer
Metastatic
cancer
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16. Combination Therapies
Prednisone
Dacarbazine Cyclophosphamide
Doxorubicin 16

17. Total Synthesis : Vinblastine
Synthesis of Catharanthine
Synthesis of Vinblastine
Coupling of Vinblastine with
Catharanthine
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18. Synthesis of Catharanthine Nucleus
The Chemical Record, Vol. 10, 101–118 (2010) © 2010 The Japan Chemical Journal Forum and Wiley Periodicals, Inc
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19. Synthesis of Vindoline Nucleus
The Chemical Record, Vol. 10, 101–118 (2010) © 2010 The Japan Chemical Journal Forum and Wiley Periodicals, Inc 19

20. Coupling of Catharanthine with Vinblastine
Exclusive formation of Natural C16’
Sterochemistry
20

21. Continue..
21

22. Emerging Vinblastine-related compounds
Aromatic Addition
Deoxygenation or
Fluorination
Coupling with Amino
acids or Peptides 22

23. Modification to Vindoline Nucleus
6-7 Double bond
modification
R1=OH, R2=H
R1=H, R2=OH
R1=H, R2=Cl
The Modification has shown 100 folds less activity than Vinblastine
6-7 Double Bond Modification
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24. Vindoline: 6-7 Double Bond Modification
I-Conversion of olefin
to cyclopropane ring
II-Reversal of 5 and 6
membered ring system
It has Shown relevant
inhibitory effect towards a
panel of cancer cell lines
It has shown similar
activity when compared to
VBL
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25. Vindoline: C4 modifications
Introduction of a
C4 methyl ester
C4
• Same potency as the natural product
• Lower metabolic lability compared to the
natural C4 acetate compound
Incorporation Of Methyl amine
forms fused ring – a N-methyl lactam
- at C3/C4 positions
• Improve the metabolic stability of VBL
• The new derivatives (a , b) are resistant to
hydrolysis, they do not significantly
reduce the cancer cell growth
C4
a. R= H
b. R=Et
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26. Vindoline: C5 Modification
The introduction of vindoline total synthesis procedure led to develop C5-
substituted vinblastine derivatives.
a. R = H
b. R=Me
c. R = Et
The C5 position should not be changed, otherwise the
antiproliferative properties will lost
C5
Robertson WM, et al. Total Synthesis and Evaluation of a Key Series of C5-Substituted Vinblastine Derivatives. J. Am. Chem. Soc. 2010
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27. Modification to the Catharanthine Nucleus
1. R=NH2
2. R=N3
3. R=SCN
4. R=NCS
5. R=NHCOIsoindoline
C20’
• 1 -Deactivates the Catharanthine nucleus, Anti
proliferative activity is lost.
• Amine → urea analogue, the antiproliferative activity
increases
• 2,3,4- derivatives has shown 10- or 100-fold less
potent than VBL
• 5- has shown cytotoxic effects towards vinblastine-
resistant cell lines
Incorporation
of C20’ ethyl
group
cis-fused six-membered ring leads to
a novel analogue
10-fold more potent than VBL
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28. Catharanthine: C10 Modification
1. R=F
2. R=Cl
3. R=Br
4. R=Me
5. R=MeO
Compound 10’-fluorovinblastine
Good cytotoxic properties
both a sensitive and a VBL-resistant tumor
cell lines
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29. Drug targeting approach
Vintafolide
• Conjugation
(desacetylvinblastine
hydrazide +folic acid).
• Itallows selective delivery
of folate receptor-targeted
anticancer drugs
Vinblastine
Folic Acid
29Pal SE, et al. Multicenter trial of EC145 in advanced, folate-receptor positive adenocarcinoma of the lung. J Thorac Oncol. 2012; 7:1618–1621

30. VBL-PHF-Trastuzumab
Antibody-drug
conjugates (ADCs)
VBL conjugated with
trastuzumab, in a ratio of 20:1
This platform exhibited
• High antigen-binding affinity,
• An excellent pharmacokinetic
profile
• Antigen-dependent efficacy,
• Tumor accumulation in
multiple tumor xenograft
models.
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A Polymer-Based Antibody-Vinca Drug Conjugate Platform:. Alexander Cancer Res. 2015; 75(16):3365-72

31. Conclusion
• Vinca Alkaloids constitute the first class of mitotic inhibitor, acting as tubulin-targeting
anticancer drugs introduced in therapy.
• Further investigations, accumulating evidence suggests that they act by inhibiting not
only tumor growth but also malignant angiogenesis.
• Efforts towards the development of novel and beneficial strategies to reduce the toxicity
and enhance the therapeutic effect of Vinca Alkaloids.
• Some deep-seated or peripheral modifications to either the catharanthine nucleus or the
vindoline nucleus have given access to a new generation of VBL derivatives endowed
with improved cytotoxic properties.
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32. References
 Ferlay J, Soerjomataram I, Ervik M, et al. GLOBOCAN 2012 v1.0, Cancer Incidence and Mortality Worldwide:
IARC Cancer Base No. 11 Lyon, France: International Agency for Research on Cancer; 2013.
 Historical Review of Vinca Alkaloids. Acta Radiologica: Diagnosis. 1969; 8:7-12.
 Ravina Enrique (2011). The evolution of drug discovery: from traditional medicines to modern drugs (1. Aufl.
ed.). Weinheim: Wiley-VCH. pp. 157–159.
 Kufe DW, Pollock, RE, Weichsel Baum RR et al. 6th ed. Hamilton (ON): BC Decker Inc; 2003. Holland-Frei
cancer medicine.
 Fahy J. Modifications in the “upper” velbenamine part of the Vinca alkaloids have major implications for tubulin
interacting activities. Curr. Pharm. Des. 2001; 7:1181–97.
 Desai A. & Mitchison TJ. Microtubule polymerization dynamics". Annu Rev Cell Dev Biol 1997; 3:83–117.
 Pellegrini F, Budman DR. Review: tubulin function, actions of antitubulin drugs, and new drug development.
Cancer Invest 2005; 23:264-273.
 WHO Model List of Essential Medicines, 20th edition List..
 Sasaki Y, Kato D, Boger DL. Asymmetric Total Synthesis of Vindorosine, Vindoline, and Key Vinblastine
Analogues. J. Am.Chem. Soc. 2010; 132:13533–13544.
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33. Continue
 Keglevich P, Hazai, L, Kalaus G, et al. Cyclopropanation of some alkaloids. Pol. Chem. Eng. 2015; 59:1-15.
 Schleicher KD, Sasaki Y, Tam A, et al. Total Synthesis and Evaluation of Vinblastine Analogues Containing
Systematic Deep-Seated Modifications in the Vindoline Subunit Ring System: Core Redesign. J. Med. Chem.
2013; 56:483-495.
 Yang S, Sankar K, Skepper CK, et al. Total synthesis of a key series of vinblastines modified at C4 that define
the importance and surprising trends in activity. Chem. Sci. 2017; 8:1560-1569.
 Vlahov IR, Santhapuram HK, Kleindl PJ, et al. Design and regioselective synthesis of a new generation of
targeted chemotherapeutics. Part 1: EC145, a folic acid conjugate of desacetylvinblastine monohydrazide.
Bioorg. Med. Chem. Lett. 2006;16:5093-5096.
 S Yokoshima,et al ,Total Synthesis of (+)-Vinblastine: Control of the Stereochemistry at C18′, The Japan
Chemical Journal Forum and Wiley Periodicals, Inc.The Chemical Record, Vol. 10, 101–118 (2010).
 Ishikawa, et al, Total Synthesis of Vinblastine, Vincristine, Related Natural Products, and Key Structural
Analogues,Journel of American chemical society,Vol. 131, no. 13, 2009.
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34. Thank you
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