Aminopropylindenes derived from Grundmann's ketone as a novel chemotype of oxidosqualene cyclase inhibitors

Abstract

A series of aminopropylindenes, designed as mimics of a cationic high energy intermediate in the oxidosqualene cyclase(1) (OSC)-mediated cyclization of 2,3-oxidosqualen to lanosterol was prepared from Grundmann's ketone. Screening on OSCs from five different organisms revealed interesting activities and selectivities of some of the compounds. A N,N-dimethylaminopropyl derivative showed promising inhibition of Trypanosoma cruzi OSC in combination with low cytotoxicity, and showed significant reduction of cholesterol biosynthesis in a human cell line.

7-Aza-des-A-steroids with Antimicrobial and Cytotoxic Activity

“…Grundmann’s ketone ( 1 ) [14] was obtained in a high yield by ozonolysis of cholecalciferol (vitamin D 3 ), by instead using our improved workup procedure (treatment of the ozonolysis mixture with water, followed by extraction with pentane [10]). For the annulation of the pyridine ring we investigated two different approaches.…”

“…Bioactive compounds derived from Grundmann’s ketone: the aminoalcohol A [9] is a selective inhibitor of human sterol Δ8,7-isomerase, the aminopropylindene B [10] is an inhibitor of oxidosqualene cyclases from various organisms, the trans -dinitrile C [11] shows cytotoxicity.…”

“…In recent investigations we demonstrated that secosteroids, derived from Grundmann’s ketone ( 1 ), covering the rings C+D as well as the aliphatic side chain of steroids, and containing amino ( A ) [9] or aminopropyl substituents ( B ) [10], are potent inhibitors of enzymes in sterol biosynthesis, whereas the trans -dinitrile C shows moderate cytotoxicity, and its cis -isomer is inactive [11] (Fig. 1).…”

“…The nitrogen atom is located at a position representing C-7 of steroids, and thus we expected that this azasteroid or its quaternary N -methyl derivative might interact with ergosterol biosynthesis in fungi or cholesterol biosynthesis in human cells by mimicking one of the numerous carbocationic HEIs [10, 13] of the enzymatic steps in the post-squalene part of sterol biosynthesis.…”

Fungal sterol C22-desaturase is not an antimycotic target as shown by selective inhibitors and testing on clinical isolates

“…Our efforts led to the discovery of new, selective cholesterol biosynthesis inhibitors targeting the enzymes oxidosqualene cyclase (OSC) [14], sterol D 8/7 -isomerase [15,16], sterol C5-desaturase as well as D 24 -desaturase (inhibited by lathosterol side chain amides depending on the size of the Nalkyl residue) [17], and 7-dehydrocholesterol reductase (7-DHCR) [18]. Furthermore, new ergosterol biosynthesis inhibitors with distinct targets like sterol D 14 -reductase [19], sterol C24-methyltransferase (24-SMT) [20], sterol D 8/7 -isomerase [19,21], but also with unidentified target(s) [22] were developed.…”