Design and Total Synthesis of a Superior Family of Epothilone Analogues, which Eliminate Xenograft Tumors to a Nonrelapsable State

Abstract

Das molekulare Editieren von Epothilon B (aus einem Myxobakterium) führte zu einem 26-Trifluoranalogon, das bei der Behandlung von Xenotransplantat-Tumoren in Nacktmäusen bemerkenswert wirksam ist. Dieses Ergebnis unterstreicht das Potenzial der gerichteten vielstufigen Totalsynthese für die Suche nach neuen Wirkstoffen, wie von Danishefsky et al. auf den folgenden Seiten diskutiert wird.

The Chemistry and Biology of Epothilones—The Wheel Keeps Turning

“…[133,135] Unfortunately, 41 in these experiments was also associated with significant toxicity, which may represent a serious drawback in the development of the compound as a potential drug candidate. [136] Nevertheless, the compound (as KOS-1584) has been promoted to clinical development status and is currently undergoing phase I clinical trials.…”

“…[135,141,142] The synthesis of 42 follows the same synthetic route as that of 41, except that the "C10-C15" fragment 48 is replaced by its corresponding trifluoro derivative 53.…”

“…[102a, 135] While fludelone exhibits similar in vitro antiproliferative activity to Epo D and thus is somewhat less active than 41, the presence of the trifluoromethyl group leads to a substantial increase in metabolic stability in mouse plasma and also human liver microsomes. [141] Most importantly, however, fludelone exhibits exquisite in vivo antitumor activity in a variety of mouse models of human cancer with excellent tolerability.…”

Synthetic Applications of β‐Fluoroalkylated α,β‐Unsaturated Carbonyl Compounds

“…[25] Such work opens the way of the applications of b-fluoroalkylated a,b-unsaturated carbonyl compounds into multistep syntheses of fluorinated analogues of natural compounds.…”

The 2006 Benjamin Franklin Medal in Chemistry presented to Samuel J. Danishefsky, Ph.D.

“…This again proved correct, as potency was restored, with the additional benefit of having improved the safety profile further. This compound is dramatically effective against taxol-resistant tumors [8]. …”