Synthesis of bioisosteric 5-sulfa-rutaecarpine derivatives

Abstract

Rutaecarpine (Evodia rutaecarpa) derivatives were synthesized by bioisosteric replacements of the quinazolone moiety of the pentacyclic system with benzothiadiazine 1,1-dioxide. Syntheses were performed efficiently by formation of phenylhydrazones via active methylene group transformations of pyrrolo-and pyrido[1,2-b]1,2,4-benzothiadiazine 5,5-dioxides, and subsequent Fischer-indolization. Preliminary testing of compound 3 showed cytotoxic activity against HeLa cells and apoptosis inducing effect.

Progress in Studies on Rutaecarpine. II.—Synthesis and Structure-Biological Activity Relationships

“…Bioisosteric replacement of the quinazolinone moiety of the pentacyclic system with benzothiadiazine 1,1-dioxide has been pursued [48] (Scheme 10). Bubenyák et al reported a condensation of benzothiadiazine 1,1-dioxide analogue 23 with phenyldiazonium chloride led to a phenylhydrazone derivative, which was subjected to Fischer indole synthesis to afford the corresponding 5-sulfarutaecarpine ( 24 ).…”

“…It should be noted that an isostere 24 with a sulfone moiety was not as active as rutaecarpine. The percentage of apoptotic cells corresponding to the sub-GI phase of 5-sulfarutaecarpine was found to be 29.2%, which compares with the 14.5% of rutaecarpine [48]. In addition, the hybrids 27a showed an increase of cytotoxic activities against HeLa cells and apoptosis inducing effects at a concentration comparable to that of etoposide.…”

Synthesis and molecular docking studies of novel tricyclic and angular tetracyclic benzothiadiazines via sp3‐C‐Hactivation as potential colon cancer inhibitors

“…Gyűjtő et al synthesized several benzothiadiazines via the lithiation method by reacting 2‐bromo benzaldehyde with ethylene glycol in toluene at reflux temperature in the presence of p ‐toluenesulfonic acid to produce ortho ‐brominated acetal‐protected benzaldehyde (2‐bromo benzyl–1,3‐dioxolane) [11]. Tricyclic benzothiadiazines were synthesized starting from veleroactam and 2‐nitrobenzene sulfonyl chloride [12]. These two last methods used prefunctionalized starting materials.…”