Synthesis and biological evaluation of vinca alkaloids and phomopsin hybrids.
Ten hybrids of vinca alkaloids and phomopsin A have been synthesized by linking the octahydrophomopsin lateral chain to the tertiary amine of the cleavamine moiety of anhydrovinblastine (AVLB) and vinorelbine. These compounds have been elaborated in order to obtain original products that may interfere with both binding sites of vinblastine (VLB) and phomopsin in tubulin. Although NMR and molecular modeling studies have shown that the orientation of the added peptide chains of these hybrids is not the same as those of phomopsin A, most of them are very potent inhibitors of microtubules assembly and they present good cytotoxicity against KB cell line. These interesting biological activities may eventually be explained by the fact that their lateral chain resides in a pocket distinct from that of the phomopsin A peptide, at the interface of tubulins beta and alpha.
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Institut de Chimie des Substances Naturelles, UPR2301, CNRS, 1 Avenue de la Terrasse, 91198 Gif-sur-Yvette, France.
Roussi
Fanny
F
Cormier
Anthony
A
Thoret
Sylviane
S
Knossow
Marcel
M
Guénard
Daniel
D
Guéritte
Françoise
F
D050256:Antimitotic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D016923:Cell Death / Q000187:drug effects; D002460:Cell Line; D020128:Inhibitory Concentration 50; D009682:Magnetic Resonance Spectroscopy; D008870:Microtubules / Q000187:drug effects / Q000378:metabolism; D015394:Molecular Structure; D009183:Mycotoxins / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D014404:Tubulin / Q000737:chemistry / Q000378:metabolism; D050257:Tubulin Modulators / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity; D014747:Vinblastine / Q000031:analogs & derivatives / Q000737:chemistry; D014748:Vinca Alkaloids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D000077235:Vinorelbine; D009842:Oligopeptides
D050256:Antimitotic Agents; D009183:Mycotoxins; D014404:Tubulin; D050257:Tubulin Modulators; D014747:Vinblastine; D014748:Vinca Alkaloids; D000077235:Vinorelbine; C035753:phomopsin; D009842:Oligopeptides