- Discovery of 5-(2-chloro-4′-(1H-imidazol-1-yl)-[1,1′-biphenyl]-4-yl)-1H-tetrazole as potent and orally efficacious S-nitrosoglutathione reductase (GSNOR) inhibitors for the potential treatment of COPD
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Endogenous nitrosothiols (SNOs) including S-nitrosoglutathione (GSNO) serve as reservoir for bioavailable nitric oxide (NO) and mediate NO-based signaling, inflammatory status and smooth muscle function in the lung. GSNOR inhibition increases pulmonary GS
- Muthukaman, Nagarajan,Deshmukh, Sanjay,Tondlekar, Shital,Tambe, Macchindra,Pisal, Dnyandeo,Sarode, Neelam,Mhatre, Siddharth,Chakraborti, Samitabh,Shah, Daisy,Bhosale, Vikram M.,Kulkarni, Abhay,Mahat, Mahamad Yunnus A.,Jadhav, Satyawan B.,Gudi, Girish S.,Khairatkar-Joshi, Neelima,Gharat, Laxmikant A.
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p. 3766 - 3773
(2018/10/20)
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- Modular synthesis of phenanthro[9,10-c]thiophenes by a sequence of C-H activation, suzuki cross-coupling and photocyclization reactions
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A total number of 15 different 3,4-diarylthiophenes were synthesized, which bear a chlorine atom in ortho-position of one of the aryl substituents. One aryl group was introduced by an oxidative cross-coupling reaction, involving a C-H activation at C4(3) of the thiophene core. The other aryl group was in most cases introduced by a Suzuki cross-coupling reaction, which succeeded the oxidative cross-coupling step. Photocyclization reactions of the 3,4-diarylthiophenes were performed in a solvent mixture of benzene and acetonitrile (50:50 v/v) at λ=254 nm and proceeded to the title compounds in yields of 60-82%. The selectivity of the photocyclization was determined at the ortho-chloro-substituted aryl ring by the position of the chlorine substituent. At the other ring, a single regioisomer was observed for phenyl and para-substituted phenyl groups. For 2-naphthyl and ortho-substituted phenyl rings a clear preference was observed in favor of a major regioisomer, while meta-substitution in the phenyl ring led to a about 1:1 mixture of 5- and 7-substituted phenanthro[9,10-c]thiophenes. Mechanistically, the photocyclization is likely to occur as a photochemically allowed, conrotatory [(4n+2)π] process accompanied by elimination of HCl. It was shown for two phenanthro[9,10-c]thiophene products that they can be readily brominated in positions C1 and C3 (74-77%), which in turn allows for further functionalization at these positions, for example, in the course of halogen-metal exchange and polymerization reactions. Three C-C bond formation reactions are successively coupled in a convergent synthesis of phenanthro[9,10-c]thiophenes A. The key reaction is an unprecedented photocyclization of precursors B, which proceeds cleanly at λ=254 nm (60-82% yield). Diarylthiophenes B are conveniently assembled employing a sequence of oxidative and regular Suzuki cross-coupling reactions.
- Schnapperelle, Ingo,Bach, Thorsten
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supporting information
p. 9725 - 9732
(2014/08/18)
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