(S)-tetrahydro Angustine derivative, and preparation method and use thereof

Abstract

The invention provides an (S)-tetrahydro Anthusine derivative and a pharmaceutically acceptable salt thereof. The (S)-tetrahydro Anthusine derivative is obtained through a series of structure modifications of strictosidine used as a starting material, and the strictosidine is synthesized by through catalyzing tryptamine and ring-split strychnine by strictosidine synthase. Monochiral polycyclic mother nucleus compounds which are difficult to synthesize through conventional medicinal chemistry are synthesized in the invention, and the compounds have outstanding in vitro topoisomerase I inhibition activity and in vitro anti-HepG2 tumor activity, and can be used in the preparation of topoisomerase I inhibitor anticancer drugs. The general structure of the (S)-tetrahydro Anthusine derivative isrepresented by formula (I) shown in the description.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry and pharmacology, and relates to a (S)-tetrahydro Angustine derivative and its preparation, as well as the application of the compound as a topoisomerase I inhibitor in the preparation of antitumor drugs. Background technique [0002] Strictosidine synthase (STR) is one of the important enzymes in the biosynthesis of monoterpene indole alkaloids, and it is the first enzyme found in nature that can catalyze the Pictet-Spengler (PS) reaction. The enzyme catalyzes the PS reaction of tryptamine and cleaved strychnine to obtain 3α(S)-isosidine, and 3α(S)-isosidine is the precursor for the biosynthesis of more than 2000 alkaloids. These alkaloids often have a wide range of activities, such as ventolin, silauwolfine, and amoline for vasodilation; quinine for antimalarial effects; vinblastine for antitumor effects, etc. are some commonly used clinical drugs . Although the chemical method can also cata...

AI Technical Summary

Problems solved by technology

[0004] Tetrahydroangustine alkaloids are widely distributed in Naucleaceae plants, and their indolo[2':3',3:4]pyrido[1,2-b]naphthyridine core structure has attracted chemists Note that several total synthetic methods have also been proposed, but there are problems such as long reaction routes, harsh reaction conditions, and low yields, and the chiral synthesis of (S)-tetrahydro Angustine alkaloids has never been reported.

In addition, tetrahydro-Angustine alkaloids have only been reported to have anti-T-24, MK tumor cell proliferation activity and anti-inflammatory activity, and their pharmacological activities remain to be explored

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