149882-10-0Relevant articles and documents
Antiangiogenic combination therapy for the treatment of cancer
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, (2008/06/13)
The present invention provides combinations of a DNA topoisomerase I inhibiting agent and a selective COX-2 inhibiting agent for preventing, treating, and/or reducing the risk of developing a neoplasia disorder in a mammal.
A general synthetic approach to the (20s)-camptothecin family of antitumor agents by a regiocontrolled cascade radical cyclization of aryl isonitriles
Josien, Hubert,Ko, Sung-Bo,Bom, David,Curran, Dennis P.
, p. 67 - 83 (2007/10/03)
A general and efficient synthesis of (20S)-camptothecin (1a) is reported. A key common intermediate containing the pyridone and lactone (DE) rings of camptothecin and most derivatives was constructed from 2-trimethylsilyl-6-methoxypyridine by a series of metalation reactions and a Heck cyclization to provide an achiral bicyclic enol ether. Sharpless asymmetric dihydroxylation followed by lactol oxidation and iododesilylation produced the key intermediate in 94% enantiomeric excess. Alkylation with prop-argyl bromide and a cascade radical reaction with phenyl isonitrile then produced 1a. About 20 other penta-and hexacyclic analogues of camptothecin with differing single or multiple substituents at C7, C9, C10, C11, and/or C12 were made by changing the propargylating agent and the isonitrile. Included among these are several drug candidates and the approved drugs topotecan and irinotecan. The synthesis of the prodrug irinotecan is a direct one that does not pass through the active metabolite. The use of ortho-trimethylsilyl-substituted isonitriles allows the regioselective synthesis of camptothecin analogues in cases where isomeric mixtures are formed from the parent isonitriles. The synthesis of the derivatives relies on the broad scope and functional group tolerance of the key cascade radical reaction.
Convergent catalytic asymmetric synthesis of camptothecin analog GI147211C
Fang, Francis G.,Bankston, Donald D.,Huie, Edward M.,Johnson, M. Ross,Kang, Myung-Chol,LeHoullier, Craig S.,Lewis, George C.,Lovelace, Thomas C.,Lowery, Melissa W.,McDougald, Darryl L.,Meerholz, Clive A.,Partridge, John J.,Sharp, Matthew J.,Xie, Shiping
, p. 10953 - 10970 (2007/10/03)
The topoisomerase I inhibitor GI147211C (4) was discovered at Glaxo Wellcome and shown to have promising anti-cancer properties. In order to fully assess the clinical potential of 4, an improved synthesis of the drug substance was required. Herein is described a convergent catalytic asymmetric synthesis of 4 which utilizes as key steps, two Heck reactions, a Sharpless asymmetric dihydroxylation reaction, and a Mitsunobu reaction. A 2-chloroquinoline is shown to be a viable substrate for the final Heck reaction to generate the camptothecin nucleus.
Kaskaden-Radikalreaktionen von Isocyaniden: eine zweite Generation der Synthese von (20S)-Camtothecin, Topotecan, Irinotecan und G1-147211C
Curran, Dennis P.,Ko, Sung-Bo,Josien, Hubert
, p. 2948 - 2950 (2007/10/03)
Keywords: Camptothecin; Isocyanide; Kaskadenreaktionen; Radikale
Synthesis and Antitumor Activity of Novel Water Soluble Derivatives of Camptothecin as Specific Inhibitors of Topoisomerase I
Luzzio, Michael J.,Besterman, Jeffrey M.,Emerson, David L.,Evans, Michael G.,Lackey, Karen,et al.
, p. 395 - 401 (2007/10/02)
The synthesis and antitumor activities of the novel water soluble camptothecin derivatives 7--10,11-(methylenedioxy)-(20S)-camptothecin trifluoroacetate (6) and 7--10,11-(ethylenedioxy)-(20S)-camptothecin trifluoroacetate (7) are described.The solubilities of compounds 6 and 7 were measured to be 4.5 and 5.8 mg/mL, respectively, in pH 5 acetate buffer in contrast to 0.003 mg/mL for camptothecin in the same buffer.In the purified topoisomerase I cleavable complex enzyme assay, compounds 6 and 7 demonstrated potent inhibition of topoisomerase I with IC50's of 300 and 416 nM, respectively, in comparison to 679 nM for camptothecin and 1028 nM for topotecan.In human tumor cell cytotoxicity assays, compounds 6 and 7 demonstrated potent antitumor activity against ovarian (SKOV3), ovarian with upregulated MDRp-glycoprotein (SKVLB), melanoma (LOX), breast (T47D), and colon (HT29) with IC50's ranging from 0.5 to 102 nM.Compounds 6 and 7 induced tumor regressions in the HT29 human colon tumor xenograft model and demonstrated similar rank order of potency compared to in vitro assay results.
