Synthesis and thromboxane synthetase inhibitory activity of di- or tetrahydrobenzo[b]thiophenecarboxylic acid derivatives

Amemiya, Yoshiya; Terada, Atsusuke; Wachi, Kazuyuki; Miyazawa, H.; Hatakeyama, Naoko; Matsuda, Kazuo; Oshima, Takeshi

doi:10.1021/jm00126a020

Cited by 24 publications

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“…The synthesis of the thiol 21i is shown in Scheme . The synthesis begins with the known ketone 25 and proceeds by one-carbon homologation and deoxygenatation. Once the alcohol was protected as a tert -butyldimethylsilyl ether, the carboxyl group was introduced by selective lithiation of the 5-position of the thiophene.…”

Section: Chemistrymentioning

confidence: 99%

Protein Structure-Based Design, Synthesis, and Biological Evaluation of 5-Thia-2,6-diamino-4(3H)-oxopyrimidines: Potent Inhibitors of Glycinamide Ribonucleotide Transformylase with Potent Cell Growth Inhibition

et al. 1997

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The design, synthesis, biochemical, and biological evaluation of a novel series of 5-thia-2,6-diamino-4(3H)-oxopyrimidine inhibitors of glycinamide ribonucleotide transformylase (GART) are described. The compounds were designed using the X-ray crystal structure of human GART. The monocyclic 5-thiapyrimidinones were synthesized by coupling an alkyl thiol with 5-bromo-2, 6-diamino-4(3H)-pyrimidinone, 20. The bicyclic compounds were prepared in both racemic and diastereomerically pure forms using two distinct synthetic routes. The compounds were found to have human GART KiS ranging from 30 microM to 2 nM. The compounds inhibited the growth of both L1210 and CCRF-CEM cells in culture with potencies down to the low nanomolar range and were found to be selective for the de novo purine biosynthesis pathway. The most potent inhibitors had 2,5-disubstituted thiophene rings attached to the glutamate moiety. Placement of a methyl substituent at the 4-position of the thiophene ring to give compounds 10, 18, and 19 resulted in inhibitors with significantly decreased mFBP affinity.

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Section: Chemistrymentioning

confidence: 99%

Protein Structure-Based Design, Synthesis, and Biological Evaluation of 5-Thia-2,6-diamino-4(3H)-oxopyrimidines: Potent Inhibitors of Glycinamide Ribonucleotide Transformylase with Potent Cell Growth Inhibition

et al. 1997

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“…and a carboxylic acid, attached to an aromatic ring such as benzene, benzofuran, benzothiophene, indole or indane. [9][10][11][12][13] First, we synthesized five compounds, in which imidazole and carboxylic acid moieties were introduced at different positions on the indoline ring and examined their activities (Table 1). Compound 2 with an imidazole moiety at the 3-position and a carboxyl moiety at the 1-position showed an approximately 1.5-fold weaker inhibitory effect on arachidonate-induced aggregation than ozagrel, a selective TXA 2 synthetase inhibitor.…”

Section: Resultsmentioning

confidence: 99%

“…The position of the imidazole and the carboxylic acid on the aromatic ring and the distance between these functional groups are important for the activity of TXA 2 synthetase inhibitors. [9][10][11][12][13] Among the indoline-based derivatives, the position of two functional groups and the distance between them in compound 2 may be more favorable for interaction with TXA 2 synthetase than those in the other four compounds (3)(4)(5)(6). Compound 4 showed potent free radical scavenging activity comparable to those of ascorbic acid and a-tocopherol.…”

Section: Resultsmentioning

confidence: 99%

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A Novel Series of Thromboxane A2 Synthetase Inhibitors with Free Radical Scavenging and Anti-peroxidative Activities.

Kamiya

Shirahase

Nakamura

et al. 2001

CHEMICAL & PHARMACEUTICAL BULLETIN

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A novel series of indoline derivatives with imidazole and carboxyl moieties were synthesized and evaluated for their thromboxane A 2 (TXA 2 ) synthetase inhibiting, radical scavenging and anti-peroxidative activities. Among the compounds synthesized, 3-{5-substituted-3-[2-(imidazol-1-yl)ethyl]indolin-1-yl}propionic acids showed free radical scavenging activity and inhibitory effects on lipid-peroxidation of rat brain homogenate and on arachidonate-induced TXA 2 -dependent aggregation of rabbit platelets. The anti-platelet and anti-peroxidative activities were related to the lipophilicity of the 5-substituent. The 5-hexyloxy derivative (13) showed about 35-fold higher inhibitory activity on TXA 2 synthesis than that of ozagrel and about 100-fold higher activity on lipid peroxidation than that of a a-tocopherol. Compound 13 showed in vivo anti-thrombotic effect in mice and ex vivo anti-peroxidative activity in rats.Key words indoline derivative; thromboxane A 2 synthetase inhibitor; radical scavenger; anti-peroxidation duced with sodium cyanoborohydride (NaBH 3 CN) to corresponding indolines followed by protection with di-tert-butyl dicarbonate ((Boc) 2 O) to afford N-protected indoline derivatives (IV). Bromination of IV with CBr 4 and Ph 3 P followed by condensation with imidazole and deprotection with HCl to afford V. Target compounds (2, 7-9, 12-27) were obtained by condensation with ethyl acrylate or ethyl 3-bromopropionate followed by hydrolysis of ester precursors (VI) with NaOH.Compounds 10 and 11 were prepared from the 5-hydroxyindoline derivative (VII). Deprotection of VI (nϭ1, mϭ2, RϭOCH 2 C 6 H 5 ) was performed with trifluoroacetic acid (TFA) in anisole to afford the corresponding phenol (VII), which was condensed with the appropriate bromides followed by hydrolysis of ester precursors with NaOH to give 10 and 11.Chart 2 shows the synthetic route of 3. 5-Bromoindoline derivative (28) was reacted with CuCN in N-methylpyrrolidone to afford 5-cyanoindoline derivative (29). Hydrolysis of 29 with conc. HCl gave the corresponding carboxylic acid (30), 19) which was protected with ester and (Boc) 2 O to give 31. Bromination of 31 with CBr 4 and Ph 3 P followed by condensation with imidazole gave 32, which was deprotected with NaOH and HCl to afford 3.Chart 3 shows the synthetic route of the other indoline derivatives (4-6). The 4-substituted derivative (34a) was prepared from 33a by condensation with ethylene bromohydrin. The 5-or 6-substituted derivatives (34b, c) were obtained by reduction of the appropriate indoline carboxylate (33b, c) 19) with diisobutylaluminum hydride (DIBAL-H) or LiAlH 4 and protection with (Boc) 2 O. Bromination of 34a-c with CBr 4 and Ph 3 P followed by condensation with imidazole gave 35a-c, which were deprotected with HCl followed by condensation with ethyl bromoacetate or ethyl acrylate followed by hydrolysis of ester precursors with NaOH to afford target compounds 4-6. Results and DiscussionIn the present study, we synthesized a series of indoline derivatives and examined their...

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“…It is important to carefully control the quantity of NaBH 4 and the reaction time to prevent overreduction of 11. Exposure of 11 to a catalytic amount of p-toluenesulfonic acid (PTSA) [13] in toluene at 50 8C furnished the desired intermediate 5 (71 %). In addition, two other precursors, 12 and 13, were synthesized in four steps from 6 in 20 % and 27 % overall yields, respectively, by a similar procedure.…”

Section: Syntheses Of Precursors 5 12 and 13mentioning

confidence: 99%

Synthetic Studies Toward Harringtonolide

Cheng

Zhai

2014

Asian J Org Chem

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IntroductionIn 1978, harringtonolide (1, Figure 1) was isolated from the seeds of Cephalotaxus harringtonia (Taxaceae). The structure of this diterpenoid tropone was established by X-ray crystallographic investigations. [1] Approximately at the same time, a group of Chinese scientists [2] led by Liang and Huang reported the isolation of 1 (named as hainanolide) from the bark of the related Chinese species Cephalotaxus hainanensis as well as its structural characterization. Harringtonolide was shown to inhibit plant growth in tobaccos and beans and to cause necrosis under certain conditions. Moreover, it was found to have antineoplastic and antiviral properties. [3,4] In addition to 1, the groups of Liang [5] and then Tang [9] discovered from hainanensis hainanolidol (2), a closely related but biologically inactive carbinol, which was converted into 1 by transannular oxidation by treatment with lead tetraacetate. Results and DiscussionRetrosynthetic Analysis of Harringtonolide Mander, [6] Huang, [7] Nay, [8] and Tang [9] have reported the total syntheses or synthetic studies of 1, specifically, Mander and co-workers [6c] adopted Rh-mediated cyclopropanation and ring-expansion reaction as the key step, and Tang and co-workers [9] constructed the tropone by an intramolecular oxidopyrylium-based [5+2] cycloaddition, Although progress has been made in studies of 1, there still exists strong demand in developing new efficient synthetic approaches to this molecule in order to launch further biological studies. Our retrosynthetic analysis is outlined in Scheme 1. We envisaged that 1 could be obtained in several steps including epoxidation, endo-ring opening of an epoxide, and lactonization from tetracycle 3, which should be accessible from 4 via an intramolecular Diels-Alder reaction (IMDA) and subsequent cycloheptatrienone formation. Compound 4 could be synthesized by a [4+3] cycloaddition from ester 5, which could be derived from ketone 6. [10] Herein, we report our synthetic efforts toward harringtonolide (1).Abstract: An efficient synthesis of an oxo-bridged 7/6-bicyclic precursor that is potentially useful for the construction of harringtonolide has been realized through a [4+3] cycloaddition reaction. Meanwhile, an unexpected rearrangement reaction, which could be used for the fast assembly of spirocycles, was found during the double elimination attempts.[a] Dr.

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Synthesis and thromboxane synthetase inhibitory activity of di- or tetrahydrobenzo[b]thiophenecarboxylic acid derivatives

Cited by 24 publications

References 0 publications

Protein Structure-Based Design, Synthesis, and Biological Evaluation of 5-Thia-2,6-diamino-4(3H)-oxopyrimidines: Potent Inhibitors of Glycinamide Ribonucleotide Transformylase with Potent Cell Growth Inhibition

Protein Structure-Based Design, Synthesis, and Biological Evaluation of 5-Thia-2,6-diamino-4(3H)-oxopyrimidines: Potent Inhibitors of Glycinamide Ribonucleotide Transformylase with Potent Cell Growth Inhibition

A Novel Series of Thromboxane A2 Synthetase Inhibitors with Free Radical Scavenging and Anti-peroxidative Activities.

Synthetic Studies Toward Harringtonolide

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