The Squalestatins: Synthesis and Biological Activity of Some C3-Modified Analogs; Replacement of a Carboxylic Acid or Methyl Ester with an Isoelectronic Heterocyclic Functionality

Abstract

A series of squalestatins modified at the C3-position with a heterocyclic functionality was prepared and evaluated in vitro as inhibitors of squalene synthase (SQS). Structure-activity relationships for compounds with the 4,6-dimethyloctenoate at C6(S1 analogues) were different from those for analogues lacking the C6 ester (H1 analogues), with a greater dependence on the nature of the C3-substituent for the H1 series. Potent SQS inhibitory activity equivalent to that of H1 is retained by a C3-(tetrazol-5-yl) analogue, i.e., a carboxylic acid mimetic. The C3-methyl ester derivative is 10-fold less active than H1, and SQS inhibitory activity similar to that of the methyl ester was retained only in those C3-heterocycle-substituted H1 analogues for which electrostatic potential maps of the C3-substituent were closely similar to that of a methyl ester.

The Squalestatins: Inhibitors of Squalene Synthase. Enzyme Inhibitory Activities and in Vivo Evaluation of C3-Modified Analogues

“…In contrast, the corresponding analogues of squalestatin H1 ( 2a ) which incorporate a C6 hydroxyl group have greatly reduced SQS inhibitory activities. Furthermore, in a series of squalestatin H1 analogues incorporating heterocyclic groups directly attached to C3, only the analogue incorporating a C3 tetrazol-5-yl group, a known carboxylic acid mimetic, retains potent SQS inhibitory activity . These results, together with those previously reported 11 for the squalestatin methyl ester derivatives, suggest that an acidic group must be present at C3 for significant SQS inhibitory activity to be retained in compounds lacking the 4,6-dimethyloctenoate ester group at C6.…”

“…As a part of our chemical program aimed at the modification of the complex squalestatin structure and the identification of the key structural features responsible for the biological activity, we have reported on the C1 chain-length requirements; on the role of the tricarboxylic acid moiety; on C6 and C7 modifications; on the C6,C7 dideoxy, C3 decarboxy, C4 deoxy, monocyclic, acyclic, , C3 hydroxymethyl and C3 heterocyclic analogues; and on modifications at the allylic center . In addition a detailed review bringing together all the published SAR of the squalestatins and the zaragozic acids has just been completed .…”

“…Thus, esterification 11 of the C3 carboxylic acid to the 3-methyl ester, decarboxylation, or reduction to the hydroxymethyl 19 derivative at this position provide analogues with potent SQS inhibitory activity. Furthermore substitution of the C3 carboxylic acid in S1 by a variety of heterocyclic substituents can be well tolerated the preparation of the C3 methyl analogue of zaragozic acid A which retains SQS inhibitory activity.…”

“…Furthermore substitution of the C3 carboxylic acid in S1 by a variety of heterocyclic substituents can be well tolerated. 20 In addition researchers at Merck have reported 23 the preparation of the C3 methyl analogue of zaragozic acid A which retains SQS inhibitory activity. In this paper we report further studies at this position on squalestatins 1a and 2a and, in particular, the effect on biological activity of replacing the carboxylic acid moiety at C3 by neutral and basic groups.…”

Squalene synthase inhibitors 1998

“…The corresponding analogues of squalestatin H1 exhibited significantly reduced in vitro activity (IC 50 > 395 nM). The C3-tetrazole derivatives of both squalestatins S1 and H1 also maintained the potency of the parent compounds, however in vivo data were not presented for these compounds [10]. An additional series of C3-side modifications has also been disclosed by Merck [107].…”