The first syntheses of (*)-calanolide A and the related (*)-calanolides C and D have been carried out in a short sequence using a Lewis acid-promoted Claisen rearrangement to establish the chromene ring.The dipyranocoumarins,' a group of natural products from several tropical plants of the genus Calophyllum, are characterized by coumarin, chromane, and chromene ring systems assembled about a phloroglucinol core.= Calanolide A (1)s and inophyllum B are two dipyr-+OH Apx 1 (R-n-Pr) 2 (R=Ph) 3 ( R = P h ; X = O ) 4 (R = n-Pr; X = H, OH)anwoumarins recently identified in screening assays as potent inhibitors of human immunodeficiency virus-1 reverse transcriptase (HIV-1 RT).6J As with other nonnucleoside HIV-1 RT inhibitors8 such as TIBOg and nevirapine,1° RT mutants resistant to calanolide A and inophyllum B have quickly been f o~n d .~J l However, these dipyranocoumarins differ from the other non-nucleosides in the distinct pattern of amino acid changes required to confer resistance,7J1 indicating that the RT binding sites for these compounds12 are overlapping but not identical.Abstract published in Advance ACS Abstracts, September 15,1993.(1) At the advice of a reviewer we use the generic name dipyranocoumarins to describe this group of structurally analogous but etymologically heterogeneous natural products, which includes the inophyllums,P.' costatolide: cordatolides,' calanolides,B and others.(2) Polonsky, J.Bull.Soc. Chim.Fr. 1956,914. Polons&l.;Baskevit.ch,
The further evolution of the imidazole-5-acrylic acid series of nonpeptide angiotensin II receptor antagonists is detailed (for Part 1, see: J. Med. Chem. 1992, 35, 3858). Modifications of the N-benzyl ring substitution were undertaken in an effort to mimic the Tyr4 residue of angiotensin II. Introduction of a p-carboxylic acid on the N-benzyl ring resulted in the discovery of compounds with nanomolar affinity for the receptor and good oral activity. SAR studies of these potent antagonists revealed that the thienyl ring, the (E)-acrylic acid, and the imidazole ring in addition to the two acid groups were important for high potency. Also, overlay comparisons of the parent diacid with both angiotensin II and a representative biphenylyltetrazole nonpeptide angiotensin II receptor antagonist are presented. The parent diacid analog, SK&F 108566 or (E)-3-[2-butyl-1-(4-carboxybenzyl)-1H-imidazole-5-yl]-2-[(2- thienyl)methyl]propenoic acid, is currently in clinical development for the treatment of hypertension.
Structure-activity relationships (SAR) were determined for novel multisubstrate inhibitors of dopamine beta-hydroxylase (DBH; EC 1.14.17.1) by examining the effects upon in vitro inhibitory potencies resulting from structural changes at the copper-binding region of inhibitor. Attempts were made to determine replacement groups for the thione sulfur atom of the prototypical inhibitor 1-(4-hydroxybenzyl)imidazole-2-thione described previously. The synthesis and evaluation of oxygen and nitrogen analogues of the soft thione group demonstrated the sulfur atom to be necessary for optimal activity. An additional series of imidazole-2-thione relatives was prepared in an effort to probe the relationship between the pKa of the ligand group and inhibitory potency. In vitro inhibitory potency was shown not to correlate with ligand pKa over a range of approximately 10 pKa units, and a rationale for this is advanced. Additional ligand modifications were prepared in order to explore bulk tolerance at the enzyme oxygen binding site and to determine the effects of substituting a six-membered ligand group for the five-membered imidazole-2-thione ligand.
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