No abstract

The effect of structural change on the biological activity of a series of imidazothiazoles and thiazolobenzimidazoles is described. It was found that compounds with polar substituents at the 2 or 3 position of the ring system are less acutely toxic while maintaining antiinflammatory activity. Other structural changes, such as the incorporation of a gem-dimethyl substituent in the 6 position, increase acute toxicity and eliminate antiinflammatory activity. The compound with the best activity/toxicity ratio contains an alkyl sulfonyl substituent on the thiazole ring. The thiazolobenzimidazole analogues are more potent than the imidazole analogues.

The GTPase activity of tubulin can be profoundly affected by many agents, including all antitubulin drugs we have examined. We have exploited this property of tubulin to develop a relatively simple screening assay to detect new antitubulin agents among antineoplastic drugs whose mechanism of action is uncertain. As demonstrated in FIGURE 1, antimitotic agents can be distinguished from drugs with no known effect on tubulin by mere inspection of an autoradiogram prepared after thin-layer separation of guanosine diphosphate (GDP) and guanosine triphosphate (GTP). In 1 .O M monosodium glutamate there is significant hydrolysis of GTP that is associated with the formation of sheets of protofilaments. The antimitotic drugs either inhibit or stimulate G T P hydrolysis, even though all antimitotic drugs except taxol inhibit glutamateinduced polymerization. In 0.1 M glutamate, GTP hydrolysis by tubulin is minimal, but a few drugs still induce a GTPase reaction. FIGURE 2 presents the chemical structures of a number of new compounds that we have found to have substantial antitubulin activity in vitro. These drugs have also demonstrated varying degrees of antileukemic activity (murine P388) in vivo in screening tests at the National Cancer Institute.Combretastatin, isolated by G. R. Pettit from the South African tree Combreturn caflrum, is structurally reminiscent of the A and C rings of colchicine as well as the bicyclic compound 2-methoxy-5-(2', 3', 4'-trimethoxypheny1)tropone (MTPT) synthesized by T. J. Fitzgerald. Combretastatin, like colchicine and MTPT, stimulates tubulin-dependent GTP hydrolysis. The drug inhibits mitosis in L1210 cells in culture and microtubule assembly (plateau level reduced over 50% a t 4-5 p M combretastatin). It competes with colchicine (apparent Ki, 1.1 p M ) but not vinblastine in binding to tubulin.

No abstract

The synthesis of a series of 5,6-diarylpyridazinones is described. Some members of this series display an antihypertensive effect in both the spontaneously hypertensive rat (SHR) model and the deoxycorticosteroid (DOCA) model of hypertension. The most potent compounds in the series have halogen substituents on the 5,6-diphenyl rings, a beta-substituted alkyl group at the 2 position of the ring, and acetyl or cyano substituent at the 4 position.