Vinblastine-Type Antitumor Alkaloids: A Method for Creating New C17 Modified Analogues (original) (raw)
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New Antitumor Hydroxymethyl Derivatives of Vinblastine
Zenodo (CERN European Organization for Nuclear Research), 1997
New hydroxymethyl derivatives (4-6, 9, IS, 16) ofthe antitumor indole-induline alkaloids vinblastine and leurosine have been prepared. In addition to the •xpected 16, the new bisvindoline 17 has been obtained as the main product, as a result of the oxidation reaction. Vincristine {l) and vinblastine (VLB) (2), the indoleindoline alkaloids of the evergreen Catharanthus roseus (Madagascar), have well-known clinical importance in the treatment of cancer 1. In order to prepare new, potentially active or less toxic analogs, we have synthesized some new hydroxymethyl derivatives ofVLB (2) and leurosine (LEU) (3), which is another alkaloid of the plant, in two different ways: (i) by conversion of the dimer isolated from the plant and (ii) by the coupling reaction of the monomer alkaloids catharanthine and the corresponding vindoline derivatives.
Modifications on the Basic Skeletons of Vinblastine and Vincristine
Molecules, 2012
The synthetic investigation of biologically active natural compounds serves two main purposes: (i) the total synthesis of alkaloids and their analogues; (ii) modification of the structures for producing more selective, more effective, or less toxic derivatives. In the chemistry of dimeric Vinca alkaloids enormous efforts have been directed towards synthesizing new derivatives of the antitumor agents vinblastine and vincristine so as to obtain novel compounds with improved therapeutic properties.
New Method of Synthesis of Vinca Alkaloid Derivatives
Bioorganic & Medicinal Chemistry Letters, 2002
Vinblastine and vinorelbine analogues have been synthesised by reacting new versatile electrophilic vindoline derivatives with various 3-substituted indoles. The resulting compounds have been evaluated for their antimitotic properties, but exhibited less potent activities in comparison with the standard binary Vinca alkaloids. #
Preclinical antitumor activity of a new Vinca alkaloid derivative, S 12363
Cancer research, 1991
S 12363 is a new Vinca alkaloid derivative obtained by appending an optically active alpha-aminophosphonate at the C23 position of O4-deacetyl vinblastine. S 12363 was evaluated for cytotoxic and antitumor activity against a spectrum of murine and human tumors. This compound was, respectively, on average, 72- and 36-fold more cytotoxic than were vincristine and vinblastine, when tested on a panel of 2 murine and 37 human tumor cell lines using the microculture tetrazolium assay. S 12363 exhibited significant antitumor activity against murine transplantable tumors (i.p. and s.c. P388 leukemia, i.p. L1210 leukemia, i.p. and i.v. B16 melanoma, i.p. M5076 sarcoma, and s.c. colon adenocarcinoma 38), while no activity was observed on s.c. Lewis lung carcinoma. S 12363, when administered i.p., showed moderate activity on human NCI-H460 lung and PANC-1 pancreas tumor xenografts in nude mice. However, when it was administered i.v., it exerted a significant activity against human HT-29 colon,...
Synthesis and SAR of vinca alkaloid analogues
Bioorganic & Medicinal Chemistry Letters, 2009
Versatile intermediates 12 0 -iodovinblastine, 12 0 -iodovincristine and 11 0 -iodovinorelbine were utilized as substrates for transition metal based chemistry which led to the preparation of novel analogues of the vinca alkaloids. The synthesis of key iodo intermediates, their transformation into final products, and the SAR based upon HeLa and MCF-7 cell toxicity assays is presented. Selected analogues 27 and 36 show promising anticancer activity in the P388 murine leukemia model.
Molecules
New Vinca alkaloid derivatives were synthesized to improve the biological activity of the natural alkaloid vindoline. To this end, experiments were performed to link vindoline with various structural units, such as amino acids, a 1,2,3-triazole derivative, morpholine, piperazine and N-methylpiperazine. The structure of the new compounds was characterized by NMR spectroscopy and mass spectrometry (MS). Several compounds exhibited in vitro antiproliferative activity against human gynecological cancer cell lines with IC50 values in the low micromolar concentration range.
1988
Reaction or the enaminc 5 with u-bromoacryljc esters or achloroacrylonitrilc and subsequent reduction with NaBH4 yielded the pcntacyclic i>-noreburnamenine derivatives 8-10 or I 1-14. rc-i f k r die Syatbesu voa Vinca-Alkaloiden uod vemandten Vcrbindungen, XXXVI".-Eine eiofacbe Syntbese einiger u-Norcbur-Ramenin-Derivate spcctivcly. A few years ago, reactions of l-ethy1-2,3,4,6,7,12-hexahydroindolo[2,3-~]quinolizine with 2-chloroacrylonitrile and methyl 2-bromoacrylate were described'). It was established that first electrophilic alkylation occurred, then, as a result of intramolecular nucleophilic attack of the N atom of the indole ring, 3,4-didehydro-14,15-dihydroeburnamenine derivatives were formed. It seemed interesting to extend the scope of these reactions to indolizino[8,7-b]indoles with an enamine moiety and a C-1 ethyl group for further investigation of structure-activity relationships (SAR). The enamine 5, unknown in the literature, was prepared by analogy to the synthesis described earlier '). Diethyl ethylmalonate (1) was alkylated with oxirane, and the disubstituted ethylmalonic ester derivative 2 was hydrolyzed without isolation in alkaline medium, then acidified. Decarboxylation of the dicarboxylic acid derivative gave the y-hydroxycarboxylic acid; elimination of water yielded 2ethyl-4-butanolide (3).
Role of vinca alkaloids and their derivatives in cancer therapy
World Journal of Advanced Research and Reviews
Vinca alkaloids and its derivatives like Vincristine, Vinblastine etc. isolated from Catharanthus roseus plants are widely used in the treatment of various types of cancers. Mode of action of Vinca alkaloids (vinblastine, vincristine, vinorelbine) is microtubule-stabilizing agents (MTAs) i.e., arrest the cell cycle via disrupting microtubule dynamics. Vincristine major side effect is neurotoxicity. Hoverer, Vincristine induce neuropathy in mice or rat, used as animal model to study effect of drugs or plants by various authors also reported in review literature. Vinca alkaloids and its derivatives were widely used drugs in combination regimens with cyclophosphamide, doxorubicin, procarbazine, Methotrexate and dacarbazine etc. in various types of cancer. In this review, we also discussed major structure modifications position of chemically synthesized vincristine and vinblastine derivatives required for potential anticancer activities. Anticancer mechanism and some major patents on vi...
Archiv der Pharmazie, 2001
In the course of an attempted synthesis of E-norvincamine (4) (-)-15-oxovincamone (7), prepared from (-)-vincamone (2), was converted by means of methanolic sodium methoxide to give the (-)-11-cis and (f)-12-trans alcohols. Alkaline hydrolysis of the dioxo compound 7 furnishes the a-0x0 acids 8 and 9 as a result of an epimerization-racemization process. uber die Synthese von Vinca-Alkaloiden und verwandten Verbindungen, XXIl I).-Einige chemische Transformationen von 15-Oxovincamon ') Wahrend einer versuchten Synthese von E-Norvincamin (4) wurde das aus (-)-Vincamon (2) hergestellte (-)-15-Oxovincamon mittels Natrium-methanolat in Methanol in den (-)-1 1 4 s-und (+)-12-trans-Alkohol iibergefiihrt.-Alkalische Hydrolyse der Dioxo-Verbindung 7 ergab die a-0x0-Sauren 8 und 9 durch einen Epimerisierungs/Racemisierungs-Pro-zeB.