Structure elucidation of A58365A and A58365B, angiotensin converting enzyme inhibitors produced by Streptomyces chromofuscus.

Abstract

A58365A and A58365B, angiotensin converting enzyme inhibitors isolated from the culture filtrate of Streptomyces chromofuscus NRRL15098, are homologous compoundsof molecular formulas C12H13NO6 and C13H15NO6. The molecular similarities of the two inhibitors were established by comparison of their 1H NMR,13C NMR,and UVspectra. Catalytic hydrogenation of A58365A led to a tetrahydro-deoxy derivative, C12Hi7NO5; extensive 1H NMR decoupling studies at 360 MHzallowed all the non-exchangeable protons of the derivative to be connected in a continuous substructure. This fragment was combined with information from other spectroscopic methods to suggest the structures for A58365A(1) and A58365B (2); the conclusions were confirmed by an X-ray crystallographic analysis of A58365A-dimethyl ester.Several inhibitors of angiotensin converting enzyme (ACE) have been discovered from fermentation sources2), many of these inhibitors exert their effect primarily through chelation of the Zn2+ in the metallodipeptidase (aspergillomarasmines A and B, L-681,176, and phenacein). Previous papers from these laboratories have described the development of a high-volume, agar-based screen for the detection of ACEinhibitors produced by fermentations and the discovery of ACEinhibitory activity in the culture broth of Streptomyces chromofuscus NRRL150983), the conditions for the biosynthesis of the ACEinhibitors A58365A and A58365B produced by this microorganism0, and the isolation and characterization of the two ACEinhibitors from A583655). A58365Aand A58365Binhibition of ACEis not reversible by addition of divalent cations3), hence strong chelation is not characteristic of these inhibitors. Furthermore, the structures of these novel fermentation products have provided a unique insight into the stereochemical requirements of captopril-related ACEinhibitors. A58365A has been determined to be 3-carboxy-l ,2,3,5-tetrahydro-8-hydroxy-5-oxo-6-indolizinepropanoic acid (1) ; A58365B is the homologous 4-carboxy-l,3,4,6-tetrahydro-9-hydroxy-6-oxo-2if-quinolizme-7-propanoic acid (2). A58365Ais thus a naturally occurring conformationally restricted analog of 2-methylglutaryl-L-proline (3), which was a part of the structure-activity relationship studies leading to captopril (4)6).Homology of A58365A and A58365B The preliminary characterization of A58365A and A58365B indicated that the two compounds are homologs, having the molecular formulas C12H13NO6 for A58365A (m/z 268.08189 by fast atom Seeref1.

Three-component solvent-free synthesis of highly substituted bicyclic pyridines containing a ring-junction nitrogen

“…All compounds were fully characterized by spectroscopic data. The NMR spectra were recorded on a Bruker DRX500 ( 1 H: 500 MHz, 13 C: 125 MHz), chemical shifts (d) are expressed in ppm, and J values are given in Hz, CDCl 3 and DMSO-d 6 were used as solvent. IR spectra were recorded on a FT-IR Thermo Nicolet Avatar 360 using KBr pellet.…”

“…Ethyl ; 1 H NMR (500 MHz, CDCl 3 ): d = 1.20 (t, J = 6.9 Hz, 3H, CH 3 ), 1.80-1.88 (m, 2H, CH 2 ), 2.00-2.03 (m, 2H, CH 2 ), 2.41 (s, 3H, ArCH 3 ), 3.46-3.52 (m, 2H, NCH 2 ), 3.67-3.70 (m, 1H, NCH 2 ), 4.16 (t, J = 6.9 Hz, 2H, OCH 2 ), 4.48-4.51 (m, 1H, NCH 2 ), 7.22 (d, J = 7.5 Hz, 2H, ArH), 7.40 (d, J = 7.5 Hz, 2H, ArH), 7.76 (s, 1H, CH), 9.09 (br, 1H, OH), 11.65 (br, 1H, NH); 13 C HMR (125 MHz, CDCl 3 ): d = 14.6, 21.9, 25.4, 25.6, 43.5, 45.3, 61.2, 84.4 (q, J = 33.8 Hz), 96.0, 96.6, 125.0 (q, J = 292.5 Hz), 129.1, 129.4, 137.9, 141. 13 C HMR (125 MHz, CDCl 3 ): d = 14.6, 43.5, 61.9, 70.3, 85.8 (q, J = 33.8 Hz), 91.2, 99.9, 124.7 (q, J = 292.5 Hz), 128.…”

“…1), 12 ACE inhibitors (A58365A and A58365B, Fig. 1), 13 human rhinovirus 3C protease inhibitors, 14 a,b-peptide aggregation inhibitors, 15 agonists of benzodiazepine receptor, 16 calcium channel blockers, 17 cyclin-dependent kinases inhibitors, 18 GABAA receptor modulators, 19 and so on. 20 Therefore, consid-Fig.…”

Synthesis and absolute configuration of methyl (–)-(3R)-8-(4-bromophenyl)-7-(naphthalen-1-ylmethyl)-5-oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyridine-3-carboxylate

“…These range from antibacterial (Casinovi et al, 1968;Dolle & Nicolaou, 1985;Rigby & Balasubramanian, 1989) and antifungal (Cox & Hagan, 1991) agents to free-radical scavengers (Teshima et al, 1991;Rice-Evans & Burdon, 1994). Ring-fused 2-pyridinones have also attracted attention as angiotensin-converting enzyme (ACE) inhibitors (Mynderse et al, 1985;Hunt et al, 1988;O'Connor & Somers, 1985), as well as inhibitors of A-peptide aggregation (Kuner et al, 2000;Thorsett & Latimer, 2000), which is believed to play an important role in amyloid formation in Alzheimer's disease.…”

Synthesis of angiotensin-converting enzyme (ACE) inhibitors: an important class of antihypertensive drugs

“…The year of 1988 was fruitful when one focalises the advances occurred into the discussed field. Almquist and colleagues 17 It is also very important to mention the article published by researchers from the Eli Lilly laboratories regarding the elucidation of A58365A 19 and A58365B 20 19 . These compounds In the nineties, studies aimed to the synthesis of conformationally restricted inhibitors of ACE continued, and, Flynn and co-workers 22 , prepared the potent thiol containing inhibitors 22 e 23 that are useful probes for studying the active sites of metalloproteases.…”