Dihydrochelerythrine and its derivatives: Synthesis and their application as potential G-quadruplex DNA stabilizing agents

Rajesh Malhotra, Chhanda Rarhi (TCGLS Member), K V Diveshkumar, Ruhee D’cunha, Rajib Barik( TCGLS Member), Pranab Dhar (TCGLS Member), Subrata Chattopadhyay (TCGLS Member), Subho Roy (TCGLS Member), Sourav Basu, Mrinalkanti Kundu (TCGLS Member), P I Pradeepkumar, Saumen Hajra

Bioorganic & Medicinal Chemistry Volume 24, Issue 13, 1 July 2016, Pages 2887–2896

DOI: 10.1016/j.bmc.2016.04.059

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 derivative 5 via in situ generated arylborane. This compound was converted to (±)-6-acetonyldihydrochelerythrine (ADC), 3 which was then resolved by chiral prep-HPLC. The efficiency of DHCHL 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 that DHCHL is a strong G-quadruplex stabilizer with an affinity similar to that.

at of the parent alkaloid CHL. Compounds ADC and DHCHL 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; whereas DHCHL showed 30% inhibition against A431 cell line only, suggesting the compounds are indeed cancer tissue-specific.