Dihydrochelerythrine and its derivatives: Synthesis and their application as potential G-quadruplex DNA stabilizing agents. Issue 13 (1st July 2016)

• Record Type: Journal Article
• Authors: Malhotra, Rajesh; Rarhi, Chhanda; Diveshkumar, K.V.; Barik, Rajib; D'cunha, Ruhee; Dhar, Pranab; Kundu, Mrinalkanti; Chattopadhyay, Subrata; Roy, Subho; Basu, Sourav; Pradeepkumar, P.I.; Hajra, Saumen
• Is Part Of: Bioorganic & medicinal chemistry. Volume 24:Issue 13(2016)
• Page Start: 2887
• Page End: 2896
• Publication Date: 2016-07-01
• Subjects: Dihydrochelerythrine -- 6-Acetonyldihydrochelerythrine -- Suzuki coupling -- G-quadruplex -- Anti-cancer; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2016.04.059
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Abstract: A convenient route was envisaged toward the synthesis of dihydrochelerythrine (DHCHL ), 4 by intramolecular Suzuki coupling of 2-bromo- N -(2-bromobenzyl)-naphthalen-1-amine derivative5 via in situ generated arylborane. This compound was converted to (±)-6-acetonyldihydrochelerythrine (ADC ), 3 which was then resolved by chiral prep-HPLC. Efficiency ofDHCHL for the stabilization of promoter quadruplex DNA structures and a comparison study with the parent natural alkaloid chelerythrine (CHL ), 1 was performed. A thorough investigation was carried out to assess the quadruplex binding affinity by using various biophysical and biochemical studies and the binding mode was explained by using molecular modeling and dynamics studies. Results clearly indicate thatDHCHL is a strong G-quadruplex stabilizer with affinity similar to that of the parent alkaloidCHL . CompoundsADC andDHCHL were also screened against different human cancer cell lines. Among the cancer cells, (±)-ADC and its enantiomers showed varied (15–48%) inhibition against human colorectal cell line HCT116 and breast cancer cell line MDA-MB-231 albeit low enantio-specificity in the inhibitory effect; whereasDHCHL showed 30% inhibition against A431 cell line only, suggesting the compounds are indeed cancer tissue specific.