2013
DOI: 10.1016/j.ejmech.2013.03.002
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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 choles… Show more

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Cited by 15 publications
(9 citation statements)
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“…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.…”
Section: Resultsmentioning
confidence: 99%
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“…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.…”
Section: Resultsmentioning
confidence: 99%
“…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.…”
Section: Figmentioning
confidence: 99%
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“…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.…”
Section: Introductionmentioning
confidence: 99%