Of vinblastine analogue

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. 

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... 

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. ... 

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... 

Vinca alkaloids such as vinblastine (2) are also known to bind tubulin. Competitive reagents along with fluorescent and fluorescent photoaffinity analogues of vinblastine (2) were synthesised in an attempt to determine the vinca alkaloid binding site. Residues 12, 201, 211,175-213, and 363-379 of p-tubulin were implicated in the binding of this compound as... 

Details have been published of the synthesis of analogues of vinblastine by Polonovski coupling of catharanthine N-oxide and various transformation products of vindoline, and a synthesis of catharinine (vinamidine) has been... 

Miyazaki T, Yokoshima S, Simizu S, Osada H, Tokuyama H, Fukuyama T (2007) Synthesis of (+)-vinblastine and its analogues. Org Lett 9 4737-4740... 

The chemistry of catharanthine is still being vigorously investigated, in connection with the synthesis of vinblastine and its analogues. Details of some of the earlier work have now become available." New work includes the preparation" of a potentially useful keto-ester (220) from an isoxazolidine derivative (219) obtainable from catharanthine. Hydrogenolysis of (219), followed by allylic oxidation and internal Michael addition, affords (220) as a mixture of C-20 epimers (Scheme 38). Other derivatives include" 15jS-hydroxy-15,20-dihydro-... 

The Volume 37 account by Kuehne and Marko 423) has considered the history of the various approaches to the synthesis of vinblastine and related analogues. The subject has also been addressed in several other recent reviews 3,424). 

The synthesis of analogues and the various structural modifications of vinblastine, as well as the attendant evaluation of their biological activities, covering the period up to 1990, have been discussed in Volume 37 455). Other recent reviews have also addressed these issues 424,456-458). Despite a very large number of analogues prepared and evaluated, vinorelbine (Navelbine) (737) and vindesine... 

A transannular 4 + 2-cycloaddition initiates the tandem 4 + 2/3+2-cycloaddion cascade of 1,3,4-oxadiazoles (1) to yield cycloadduct intermediates (2) used for the synthesis of analogues of vinblastine (Scheme 1)." The multi-component 4+ 2/3+2-domino cycloaddition reactions of 3-nitroindole derivatives with vinyl ethers and acrylates were studied computationally and experimentally. The 4+2-reaction follows a classical concerted asynchronous process while the 3 + 2-addition involves an electron donation by an electron-deficient reaction partner. ... 

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 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 ... 

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],... 

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