The combination in one molecule of functional groups that can interact specifically with different substrate binding areas at the active site of carboxypeptidases A and B has led to the development of potent and specific inhibitors of these enzymes. 2-Benzyl-3-mercaptopropanoic acid (SQ 14,603) has a Ki of 1.1 x 10(-8) M vs. carboxypeptidase A and a Ki of 1.6 x 10(-4) M vs. the B enzyme. 2-Mercaptomethyl-5-guanidinopentanoic acid (SQ 24,798) has a Ki of 4 x 10(-10) M vs. carboxypeptidase B and a Ki of 1.2 x 10(-5) M vs. carboxypeptidase A. It is proposed that the sulfhydryl groups of these inhibitors bind to the catalytically important zinc ions of these enzymes, and that, in conjunction with the benzyl and guanidinopropyl side chains, they are responsible for their specificity.

hydroxy-5-methyl-7-methylenedibenz[¿>,g]azocme (12). To a 10-mL, round-bottomed flask under nitrogen were added 101 mg (0.25 mmol) of 9 and 3 mL of distilled CH2C12 (CaH2). The solution was cooled to 0 °C and 250 pL (0.27 mmol) of 12.5% phosgene in toluene was added. The solution was allowed to warm to room temperature overnight. The solvent was removed by rotary evaporation and the residue purified by preparative thin-layer chromatography (5:1 cyclohexane/EtOAc; Si02,0.5 mm X 20 cm X 20 cm) to yield, after recrystallization from 10:1 hexane/benzene, 83 mg (77%) of 12; field desorption mass spectrum, m/e 385 (M+); mp 147-148 °C; 1H NMR (CDC13) 1.37

A series of mercaptoacyl amino acids and related compounds was synthesized and evaluated for inhibition of angiotensin-converting enzyme (ACE) in order to determine the nature and importance of the putative interaction between ACE and the amide moiety of inhibitors such as captopril (3-mercapto-2-methylpropanoyl-L-proline). It was concluded that the interaction involves a hydrogen bond from a donor site on ACE to the oxygen of the amide carbonyl. Compounds in which the amide moiety is replaced by other groups (ester, ketone, sulfonamide) capable of accepting a hydrogen bond are effective inhibitors, but compounds in which only the geometrical features of the amide are retained are ineffective inhibitors. The presence of an NH group is not necessary for effective inhibition. The activity of a series of mercaptoacyl cycloalkyl carboxylic acids parallels the activity of the isosteric series of mercaptoacyl imino acids.

A series of novel regioisomeric tetrahydrophthalimide‐substituted indolin‐2‐ones has been prepared via the Sommelet‐Hauser type cyclization of appropriately substituted anilines as potential herbicides. The resultant indolin‐2‐ones were then regioselectively alkylated at N‐1 and C‐3 to give 1,3,3‐trisubstituted indolin‐2‐ones. The most active series was also prepared by the bis‐nitration of m‐fluorophenylacetic acid followed by reduction and cyclization to give 6‐amino‐5‐fluoroindolin‐2‐one. Elaboration to the tetrahydrophthalimide‐substituted indolin‐2‐one was followed by C‐ and N‐alkylation to give the desired compounds.

An efficient synthesis of hexahydrofluorene-2,9-dione and 7-methoxyhexahydrofluorene-2,9-dione from the appropriate phenylpyruvic acids is described. Their conversion to -bromo esters and amides as well as the intramolecular Reformatsky reaction of these substances to provide gibbane synthons is detailed.Synthetic efforts directed toward the gibberellins [gibberellic acid (1)] have led to known gibberellins,3 degradation products thereof,4 and gibbane synthons.5 Our interest in this problem lay in devising an efficient synthetic route to hexahydrofluorenones 7a and 7b, which could in turn lead to tetracyclic gibbane synthons.Although frans-2-phenyl-o-oxo-l-cyclohexanecarboxylic acid (4) had previously been cyclized to dione 7a, no yields were specified and, moreover, the acid was obtained as the minor product from the Diels-Alder reaction of 2-ethoxybutadiene and irans-cinnamic acid.6 It seemed reasonable that the corresponding cis acid 5a would be more amenable to cyclization than its trans counterpart. In addition, the fact that the dissolving metal reduction of 3,4-diphenylcyclohex-2-en-l-one (3a) affords m-3,4-diphenylcyclohexanone7 augured well for a method of preparing the requisite cis acid, since the carboxylate anion of acid 3b should play a similar role to that of the 3-phenyl substituent in ketone 3a.To this end, the condensation between p-methoxyphenylpyruvic acid and methyl vinyl ketone was achieved in aqueous methanolic sodium hydroxide, yielding 1-hydroxy-2-(p-methoxyphenyl)-5-oxo-l-cyclohexanecarboxylic acid (2c) as a single diastereomer in high yield. Several analogous annelations have been reported between phenylpyruvic acid and benzalacetone,8•9 p-methoxybenzylidene acetone,9 and ethyl(1) Taken in part from the Ph.D. thesis of , E. C.,