4,5-Diaryl-1H-pyrrole-2-carboxylates as combretastatin A-4/lamellarin T hybrids: synthesis and evaluation as anti-mitotic and cytotoxic agents.
The 4,5-diarylated-1H-pyrrole-2-carboxylates 3-8 have each been prepared as hybrids of the potent anti-mitotic agent combretastatin A-4 (1) and the similarly active marine alkaloid lamellarin T (2). The key steps involved selective lithium-for-halogen exchange at C5 within the N-PMB protected 4,5-dibromopyrrole 22 and Negishi cross-coupling of the derived zincated species with the relevant aryl iodide. The ensuing 5-aryl-4-bromopyrrole then engaged in Suzuki-Miyaura cross-coupling with the appropriate arylboronic acid to give the 4,5-diarylated pyrroles 4, 6 and 8. TFA-promoted removal of the N-PMB group within these last compounds then gave the N-unsubstituted congeners 3, 5 and 7. Compounds 3-8 have all been evaluated for their anti-mitotic and cytotoxic properties and two of them, 3 and 5, display useful activities although they are less potent than combretastatin A-4.
Banwell
Martin G
MG
Research School of Chemistry, Institute of Advanced Studies, The Australian National University, Canberra, ACT. mgb@rsc.anu.edu.au
Hamel
Ernest
E
Hockless
David C R
DC
Verdier-Pinard
Pascal
P
Willis
Anthony C
AC
Wong
David J
DJ
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D050256:Antimitotic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D002417:Cattle; D006576:Heterocyclic Compounds, 4 or More Rings / Q000737:chemistry*; D011392:Proline / Q000031:analogs & derivatives* / Q000737:chemistry; D013267:Stilbenes / Q000737:chemistry*; D014404:Tubulin / Q000187:drug effects*
D000903:Antibiotics, Antineoplastic; D050256:Antimitotic Agents; D006576:Heterocyclic Compounds, 4 or More Rings; D013267:Stilbenes; D014404:Tubulin; C512537:lamellarin T; C002986:2-pyrrolecarboxylic acid; D011392:Proline; C058728:fosbretabulin