Vinblastine, analogues

Finally, a number of model vinblastine analogues, e.g. (209), have been synthesised by condensation of vindoline with an anilinoacrylate base related to vincadifformine, but lacking ring... 

Kutney s work on the manipulation of the functional groups of vindoline, as a preliminary to the partial synthesis of vinblastine analogues, and the synthesis, in... 

The long series of experiments involving the synthesis of vinblastine analogues by the Polonovski coupling of catharanthine Nb-oxide derivatives with vindoline has culminated in the synthesis of vinblastine (290) itself, and this forms a fitting climax to any report on the past year s progress in indole alkaloid chemistry. 

SCHEME 51 Synthesis of vinblastine analogues. PIFA, bis(trifluoroacetoxy)iodobenzene HFIP, 1,1,1,3,3,3-hexafluoroisopropanol. 

Kapat A, Konig A, Montermini F, Renaud P (2011) A radical jaocedure for the anti-markovnikov hydroazidation of alkenes. J Am Chem Soc 133(35) 13890-13893 Leggans EK, Barker TJ, Duncan KK, Boger DL (2012) lron(lll)/NaBH4-mediated additions to unactivated alkenes synthesis of novel 20 -vinblastine analogues. Org Lett 14(6) 1428-1431... 

The Catharanthus (Vincd) alkaloids, vinblastine (4) and vincristine (5), are not only very useful anticancer agents, but are also bona fide lead compounds. A semisynthetic vinblastine (4) analogue, vinorelbine (52) is indicated for lung and mammary carcinomas. Vinflunine was further developed from vinorelbine, and has shown promise in phase II clinical trials. >93... 

The vinca alkaloids comprise vincristine and vinblastine. These complex, heterocyclic alkaloids are derived from the periwinkle plant. Vindesine and vi-norelbine are semisynthetic analogues. These drugs are M-phase specitic. Binding specifically to tubulin they inhibit the polymerization of microtubules. The consequent ineffective chromosome segregation initiates apoptosis for both normal and malignant cells. 

Vinca dimer indole alkaloids (e.g. vinbiastine) act as spindle poisons. They bind tubulin, inhibiting polymerisation into microtubules, the major elements of the cytoskeleton [100]. Vinblastine itself and its analogue vinoreibine (Navelbine ) [101] are marketed for cancer therapies (Fig. 36). Vinflunine (Javlor ) is a member of second-generation Vinca dimer alkaloids. This 4 -difluoro analogue is more active than vinoreibine in several cancers (Fig. 36). It is now in phase III clinical... 

Vinca dimer indole alkaloids (e.g., vinblastine) act as spindle poison. They bind tubulin, inhibiting polymerization into microtubules, major elements of the cytoske-Vinblastine itself and its analogue vinorelbine (Navelbine ) are marketed for cancer therapies (Figure 4.48). Because of the obvious difficulty in synthesizing such highly complex structures, there were no reports on the preparation of fluorinated derivatives until the remarkable work of Jacquesy s group on the synthesis in super-acidic media. 5 ... 

Drug Interactions Zidovudine Probenecid Imipenem-cilastatin Dapsone Pentamidine Flucytosine Vincristine Vinblastine Adriamycin Amphotericin B TMP-SMX Other nucleoside analogues... 

Vinblastine (6.73) is an antimitotic drug that prevents polymerization of tubulin (Figure 6.26). When incubated with tubulin, vinblastine complexes in a 1 1 ratio with tubulin proteins. By blocking polymerization, vinblastine prevents microtubule formation and therefore mitosis. In contrast, paclitaxel (Taxol, 6.74) and epothilone B (6.75) stabilize aggregated tubulin. As a result, in the presence of paclitaxel and epothilone B, cells form static bundles of microtubules that are nonfunctional. Vinblastine and paclitaxel are both approved for clinical use against cancer. Ixabepilone (6.76), an analogue of epothilone B (6.75), has been approved by the FDA for treatment of certain forms of breast cancer. The European Medicines Agency (EMEA) did not approve ixabepilone out of concern over severe side effects.27... 

HTI-286 binds to the tubulin heterodimer and induces formation of 13-membered tubulin rings [138], Photoaffinity labeling with analogues of HTI-286 mapped to residues of a-tubulin close to the interdimer interface [139], Competitive binding assays with dolastatin-10, cryptophycin A, vinblastine, PTX and colchicines, indicate that the hemiasterlins bind in a subsite of the Vinca domain, which is located at the interdimer interface [28],... 

The tubulin-binding properties of (-)-rhazinilam were discovered through screening of a number of Malaysian plant extracts [60]. Natural (-)-rhazinilam induces tubulin spiralization, inhibiting tubulin assembly in the same way as vinblastine-like alkaloids, and protects microtubules from cold disassembly such as with paclitaxel [67]. This effect has never been observed with other microtubule poisons. For this reason, and despite the in vivo inactivity of (-)-rhazinilam [67], a number of analogues have been prepared by semi-synthesis and total synthesis (see Sections 3.1.3. and 3.2.3.) in order to improve the pharmacological properties of this molecule. 

The AC of vinblastine 14, one of the best-known Vinca alkaloids, was originally established by X-ray crystallography by Moncrief and Lipscomb.89 CD experimental and theoretical studies have also been carried out for the purpose of determining the AC of vinblastine and its natural and synthetic analogues.41,90... 

Evidence for a direct correlation between the turnover number for vinblastine-stimulated ATP hydrolysis and vinblastine transport rate was provided by Ambudkar and Stein [43]. Since compounds that interact with P-gp often exhibit a high lipid-water partition coefficient and can cross the lipid bilayer by passive diffusion, the stoichiometry between ATP hydrolysis and drug transport is difficult to assess. Using a permanently charged spin-labeled analogue of verapamil that cannot cross the membrane by passive diffusion [44], a direct correlation between ATP hydrolysis and drug transport was demonstrated [45]. 

Vinblastine and vincristine have been used clinically for many years. The major importance of vinblastine is as part of a combination treatment for Hodgkin s disease, while vincristine is used in combination chemotherapy of acute lymphoblastic leukemias and lymphomas. Several analogues of the vinca alkaloids have entered clinical use or clinical trials, including vindesine (3), vinorelbine (4), " the naturally occurring anhydrovin-blastine (5), and vinflunine (6). ° Several synthetic approaches to the vinca alkaloids have been developed, especially by Kuehne, while studies of the chemistry of the alkaloids in super acidic media have yielded new alkaloids such as vinflunine. ... 

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