- A general synthetic approach to the (20s)-camptothecin family of antitumor agents by a regiocontrolled cascade radical cyclization of aryl isonitriles
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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.
- Josien, Hubert,Ko, Sung-Bo,Bom, David,Curran, Dennis P.
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- Plant Antitumor Agents. 30. Synthesis and Structure Activity of Novel Camptothecin Analogs
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A large number of camptothecin (CPT) analogs have been prepared in the 20S, 20RS, and 20R configurations with a number of ring A substituents.Topoisomerase I (T-I) inhibition data (IC50) have been obtained by standard procedures.In general, substitution at the 9 or 10 positions with amino, halogeno, or hydroxyl groups in compounds with 20S configuration results in compounds with enhanced T-1 inhibition.Compounds in the 20RS configuration were less active in vitro and in vivo and those in the 20R configuration were inactive.Compounds with 10,11-methylenedioxy substitution on ring A displayed a marked increase in potency in the T-I inhibition assay.The activities of some of the analogs as determined in a variety of in vivo assays including the L-1210 mouse leukemia assay were, in general, in accord with T-I inhibition.A number of water-soluble analogs such as 20-glycinate esters, 9-glycinamides, or hydrolyzed lactone salts were prepared and tested in in vitro and in vivo assays.In general, these compounds were less active than CPT both in terms of T-I inhibition and life prolongation in the L-1210 assay.However, certain 20-glycinate esters showed good in vivo activity after iv administration.
- Wall, Monroe E.,Wani, Mansukh C.,Nicholas, Allan W.,Manikumar, Govindarajan,Tele, Chhagan,et al.
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p. 2689 - 2700
(2007/10/02)
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- Synthesis and antitumor activity of 20(S)-camptothecin derivatives: A-ring modified and 7,10-disubstituted camptothecins
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20(S)-Camptothecin derivatives having nitro, amino, chloro, bromo, hydroxyl and methoxyl groups in the A-ring were synthesized. B-Ring hydrogenated camptothecin (2a) was converted into 10-hydroxycamptothecin (6e) by treatment with lead tetraacetate in trifluoroacetic acid. 10-Substituted derivatives (6) were obtained by a photoreaction of N-oxides (9). The cytotoxicity of the A-ring modified camptothecins was evaluated against KB cells in vitro and leukemia L1210 in mice. 7-Ethyl-10-hydroxycamptothecin (6i) was identified as a potential derivative for further modification.
- Sawada,Matsuoka,Nokata,Nagata,Furuta,Yokokura,Miyasaka
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p. 3183 - 3188
(2007/10/02)
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