No abstract

Synthesis of tetramethoxybiphenyl21 was accomplished from 4-phenylcyclohexane-1,3-dione 13 by aromatization to biphenyl 19 and reductive removal of the phenolic OH group as phenyltetrazolyl ether. Tetramethoxybiphenyls 34 and 40 were obtained from 4-phenylcyclohexenone 26 via ester 27. The tetramethoxybiphenyls 21,34, and 40, and analogs 28, 29, and 31 were evaluated for antitubulin activity and as antimitotic agents with L1210 murine leukemia cells. Compounds 31 and 34 had significant effects on the in-vitro polymerization of tubulin. Compound 31 was the most cytotoxic of the six new biphenyls studied (ICs0 for cell growth, 0 . 6~) and caused the accumulation of cells in metaphase arrest.Introduction. -The antimitotic effect of colchicine and its inhibition of migration and phagocytosis of polymorphonuclear leukocytes are attributed to its binding to tubulin, which disorients the structural organization of microtubules [ 1-41. Data collected from studies of many colchicinoids (compounds chemically related to colchicine) in assays, measuring binding to tubulin in vitro an antitumor activity in vivo [4] [5], and inhibition of

The structure of new hypotensive vasodilators, WS-1228 A and B, produced by Streptomyces aureofaciens, were determined as I and 2, respectively, on the basis of their spectral and chemical evidences. WS-1228 A (1), having N-hydroxytriazene moiety, was synthesized from (E,E,E)-2,4,7undecatrienal (4) by condensation with hydrazine hydrate followed by nitrosation.

Synthesis of deaminocolchinyl methyl ether 9 was achieved from tetramethoxy-substituted biphenyl-2-carbaldehyde 12 via tricyclic ketone 20 and 5,6-didehydro congener 11. Compound 9 was identical in every respect with material prepared from colchicine uiu 6,7-didehydro congener 10. Measuring inhibition of tubulin polymerization in vitro showed compounds 4, 5, and 9-11 of the alloseries of colchicinoids to be particularly potent inhibitors.Introduction. -A large number of synthetic and natural compounds bind to the protein tubulin and, in so doing, inhibit its polymerization in vitro [l]. This property accounts for many of the effects observed when cells are treated with this class of agents, most notably failure of mitotic spindle formation and dissolution of the interphase microtubule network. This disruption of microtubules is probably responsible for the therapeutic properties of antimitotic agents. The majority of compounds which inhibit tubulin polymerization also, despite remarkably diverse structures, competitively inhibit the binding of radiolabeled colchicine to tubulin. This implies that, despite their structural diversity, they share features that allow them to bind at a common site on the protein. The most thoroughly studied member of this class of drugs is colchicine ( = ( S ) -N-(5,6,7,9-tetrahydro-l,2,3,l0-tetramethoxy-9-oxobenzo[a]heptalen-7-yl)acetamide; 1, R' = CH,, R2 = CH,CONH, R3 = CH,O).Because of the antineoplastic potential of agents which inhibit microtubule assembly, a thorough understanding of the colchicine binding site is important. One approach to this problem is evaluation of antitubulin properties of analogs of active drugs. For example, virtually all colchicinoids summarized in structure 1, as well as the dehydro analog 2 [2], inhibit tubulin polymerization and the growth of tumor cells in vitro and, in some cases, in vivo. More drastic changes in the colchicine molecule have surprisingly little apparent effect on most of these inhibitory properties. Complete elimination of ring B yields an antimitotic compound binding at the colchicine site (2-methoxy-5-(2',3',4-trimethoxyphenyl)cyclohepta-2,4,6-trien-l-one (3)) [3] [4]. Conversion of the 7-membered 2-substituted cycloheptatrienone moiety (ring C) to a 6-membered phenyl ring yields compounds more potent than colchicine as polymerization inhibitors (allocolchicine (4) and N-acetylcolchinyl methyl ether 5) [3] [5].