A new series of the SMTP plasminogen modulators with a phenylamine-based side chain.

Haruki Koide, Keiko Hasegawa, Naoko Nishimura, Ritsuko Narasaki, Keiji Hasumi

Department of Applied Biological Science, Tokyo Noko University, Tokyo, Japan.

The Journal of antibiotics 2012 Jul

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SMTPs are a family of small-molecule plasminogen modulators that enhance plasminogen activation. SMTP-7, one of the most potent congeners, is effective in treating thrombotic cerebral infarction. The SMTP molecule consists of a tricyclic γ-lactam moiety, a geranylmethyl group, and an N-linked side chain. The presence of both an aromatic group and a negatively ionizable group in the N-linked side chain is crucial for activity. Investigations of the congeners with a phenylglycine-based side chain suggest that a phenolic hydroxy group affects potency. In this study, we isolate and characterize a series of novel SMTP congeners with a phenylamine-based N-linked side chain. Of the 11 congeners isolated, SMTP-19 (with a 4-phenylcarboxylic acid moiety), SMTP-22 (with a 3-hydroxyphenyl-4-carboxylic acid moiety) and SMTP-25 (with a 2-hydroxyphenyl-3-carboxylic acid moiety) are as potent as SMTP-7 in plasminogen-modulating activity. Their isomers with a carboxylic acid group and/or a phenolic hydroxy group at different positions have <40% of the activity of these congeners. Both SMTP-22 and SMTP-25 have >1.7 times more oxygen radical absorbance capacity as compared with SMTP-7.

Citation

Haruki Koide, Keiko Hasegawa, Naoko Nishimura, Ritsuko Narasaki, Keiji Hasumi. A new series of the SMTP plasminogen modulators with a phenylamine-based side chain. The Journal of antibiotics. 2012 Jul;65(7):361-7