Tags

Type your tag names separated by a space and hit enter

Synthesis and biological evaluation of novel A-ring modified hexacyclic camptothecin analogues.
J Med Chem. 2001 May 10; 44(10):1594-602.JM

Abstract

Eleven A-ring modified hexacyclic analogues of camptothecin (CPT) containing a 1,4-oxazine ring were synthesized from 10-hydroxycamptothecin (11a) and 7-ethyl-10-hydroxycamptothecin (3) (SN-38) in four to five steps and were subjected to the biological tests such as cytotoxicity, topoisomerase I (Topo I) inhibitory activity, acetylcholinesterase (AChE) inhibition, and stability in human plasma. Four compounds 15a, 15b, 16a, and 16c were about 2-fold more potent than topotecan and as potent as CPT toward human cancer cell lines A549, H128, WiDr, MKN45, SK-OV-3, and SK-BR-3 in vitro, even though the most active compound 15b was slightly less potent than SN-38. The potency of Topo I inhibition of these compounds showed relatively good correlation with their cytotoxicity. Most of the compounds exhibited AChE inhibitory activity weaker (9 +/- 2 to 20 +/- 3%) than CPT (23 +/- 5%) or topotecan (20 +/- 4%) and similar to SN-38 (13 +/- 2%), indicating that they might have little effect on causing early diarrhea. The stability of lactone forms of these compounds in human plasma seemed to be much higher than that of CPT and similar to that of topotecan but lower than that of SN-38. Among the new hexacyclic CPT analogues, compound 15b showed higher antitumor activity against human tumor xenograft, WiDr, in nude mice compared to that of SN-38. The most promising compound 15b has been selected for further development.

Authors+Show Affiliations

Life Science Research Center, SK Chemicals, 600 Jungja-Dong, Changan-Ku, Suwon-Si, Kyungki-Do 440-745, Korea. dkkim@skchemicals.comNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

11334569

Citation

Kim, D K., et al. "Synthesis and Biological Evaluation of Novel A-ring Modified Hexacyclic Camptothecin Analogues." Journal of Medicinal Chemistry, vol. 44, no. 10, 2001, pp. 1594-602.
Kim DK, Ryu DH, Lee JY, et al. Synthesis and biological evaluation of novel A-ring modified hexacyclic camptothecin analogues. J Med Chem. 2001;44(10):1594-602.
Kim, D. K., Ryu, D. H., Lee, J. Y., Lee, N., Kim, Y. W., Kim, J. S., Chang, K., Im, G. J., Kim, T. K., & Choi, W. S. (2001). Synthesis and biological evaluation of novel A-ring modified hexacyclic camptothecin analogues. Journal of Medicinal Chemistry, 44(10), 1594-602.
Kim DK, et al. Synthesis and Biological Evaluation of Novel A-ring Modified Hexacyclic Camptothecin Analogues. J Med Chem. 2001 May 10;44(10):1594-602. PubMed PMID: 11334569.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Synthesis and biological evaluation of novel A-ring modified hexacyclic camptothecin analogues. AU - Kim,D K, AU - Ryu,D H, AU - Lee,J Y, AU - Lee,N, AU - Kim,Y W, AU - Kim,J S, AU - Chang,K, AU - Im,G J, AU - Kim,T K, AU - Choi,W S, PY - 2001/5/4/pubmed PY - 2001/6/8/medline PY - 2001/5/4/entrez SP - 1594 EP - 602 JF - Journal of medicinal chemistry JO - J. Med. Chem. VL - 44 IS - 10 N2 - Eleven A-ring modified hexacyclic analogues of camptothecin (CPT) containing a 1,4-oxazine ring were synthesized from 10-hydroxycamptothecin (11a) and 7-ethyl-10-hydroxycamptothecin (3) (SN-38) in four to five steps and were subjected to the biological tests such as cytotoxicity, topoisomerase I (Topo I) inhibitory activity, acetylcholinesterase (AChE) inhibition, and stability in human plasma. Four compounds 15a, 15b, 16a, and 16c were about 2-fold more potent than topotecan and as potent as CPT toward human cancer cell lines A549, H128, WiDr, MKN45, SK-OV-3, and SK-BR-3 in vitro, even though the most active compound 15b was slightly less potent than SN-38. The potency of Topo I inhibition of these compounds showed relatively good correlation with their cytotoxicity. Most of the compounds exhibited AChE inhibitory activity weaker (9 +/- 2 to 20 +/- 3%) than CPT (23 +/- 5%) or topotecan (20 +/- 4%) and similar to SN-38 (13 +/- 2%), indicating that they might have little effect on causing early diarrhea. The stability of lactone forms of these compounds in human plasma seemed to be much higher than that of CPT and similar to that of topotecan but lower than that of SN-38. Among the new hexacyclic CPT analogues, compound 15b showed higher antitumor activity against human tumor xenograft, WiDr, in nude mice compared to that of SN-38. The most promising compound 15b has been selected for further development. SN - 0022-2623 UR - https://www.unboundmedicine.com/medline/citation/11334569/Synthesis_and_biological_evaluation_of_novel_A_ring_modified_hexacyclic_camptothecin_analogues_ L2 - https://dx.doi.org/10.1021/jm0004751 DB - PRIME DP - Unbound Medicine ER -