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Homocamptothecins: E‐Ring Modified CPT Analogues
Author(s) -
LAVERGNE OLIVIER,
DEMARQUAY DANIELE,
KASPRZYK PHILIP G.,
BIGG DENNIS C.H.
Publication year - 2000
Publication title -
annals of the new york academy of sciences
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.712
H-Index - 248
eISSN - 1749-6632
pISSN - 0077-8923
DOI - 10.1111/j.1749-6632.2000.tb07029.x
Subject(s) - ring (chemistry) , cleavage (geology) , chemistry , dna , stereochemistry , tumor cells , cell culture , pharmacology , biochemistry , cancer research , biology , genetics , organic chemistry , paleontology , fracture (geology)
A bstract : Homocamptothecins (hCPT) are modified camptothecins (CPT) with a seven‐membered β‐hydroxylactone instead of the naturally occurring six‐membered α‐hydroxylactone. This E‐ring modification fully conserves the ability to stabilize topo I‐DNA single‐strand breaks and stimulates high levels of DNA cleavage. A key feature is the irreversibility of E‐ring opening, which should give reduced toxicity. Substituted hCPTs have been selected for their high antiproliferative activity on a panel of tumor cell lines, including those with cross resistance, and were found to be active at very low doses in a variety of human tumor xenografts when administered orally. BN 80915, a difluoro‐hCPT, has entered clinical trials.