title: Dihydrochelerythrine and its derivatives: Synthesis and their application as potential G-quadruplex DNA stabilizing agents.
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 derivative 5 via in situ generated arylborane. This compound was converted to (±)-6-acetonyldihydrochelerythrine (ADC), 3 which was then resolved by chiral prep-HPLC. 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 affinity similar to that 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.
authors.affiliation: Department of Chemistry, Guru Jambheshwar University of Science and Technology, Hisar, Haryana 125001, India.
authors.forename: Rajesh
authors.initials: R
authors.lastname: Malhotra
authors.affiliation: Department of Chemistry, Guru Jambheshwar University of Science and Technology, Hisar, Haryana 125001, India; TCG Lifesciences Pvt. Ltd., BN-7, Salt Lake, Kolkata 700091, India.
authors.forename: Chhanda
authors.initials: C
authors.lastname: Rarhi
authors.affiliation: Department of Chemistry, Indian Institute of Technology Bombay, Mumbai 400076, India.
authors.forename: K V
authors.initials: KV
authors.lastname: Diveshkumar
authors.affiliation: TCG Lifesciences Pvt. Ltd., BN-7, Salt Lake, Kolkata 700091, India.
authors.forename: Rajib
authors.initials: R
authors.lastname: Barik
authors.affiliation: Department of Chemistry, Indian Institute of Technology Bombay, Mumbai 400076, India.
authors.forename: Ruhee
authors.initials: R
authors.lastname: D'cunha
authors.affiliation: TCG Lifesciences Pvt. Ltd., BN-7, Salt Lake, Kolkata 700091, India.
authors.forename: Pranab
authors.initials: P
authors.lastname: Dhar
authors.affiliation: TCG Lifesciences Pvt. Ltd., BN-7, Salt Lake, Kolkata 700091, India. Electronic address: mrinal.kundu@tcgls.com.
authors.forename: Mrinalkanti
authors.initials: M
authors.lastname: Kundu
authors.affiliation: TCG Lifesciences Pvt. Ltd., BN-7, Salt Lake, Kolkata 700091, India.
authors.forename: Subrata
authors.initials: S
authors.lastname: Chattopadhyay
authors.affiliation: TCG Lifesciences Pvt. Ltd., BN-7, Salt Lake, Kolkata 700091, India.
authors.forename: Subho
authors.initials: S
authors.lastname: Roy
authors.affiliation: TCG Lifesciences Pvt. Ltd., BN-7, Salt Lake, Kolkata 700091, India.
authors.forename: Sourav
authors.initials: S
authors.lastname: Basu
authors.affiliation: Department of Chemistry, Indian Institute of Technology Bombay, Mumbai 400076, India. Electronic address: pradeep@chem.iitb.ac.in.
authors.forename: P I
authors.initials: PI
authors.lastname: Pradeepkumar
authors.affiliation: Centre of Biomedical Research, SGPGIMS Campus, Lucknow 226014, India. Electronic address: saumen.hajra@cbmr.res.in.
authors.forename: Saumen
authors.initials: S
authors.lastname: Hajra
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D053119:Benzophenanthridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002942:Circular Dichroism; D004247:DNA / Q000737:chemistry* / Q000378:metabolism*; D054856:G-Quadruplexes; D042822:Genomic Instability / Q000187:drug effects*; D045325:HCT116 Cells; D006801:Humans; D056004:Molecular Dynamics Simulation; D015394:Molecular Structure
chemical_list: D000970:Antineoplastic Agents; D053119:Benzophenanthridines; C524982:dihydrochelerythrine; D004247:DNA
keywords: 6-Acetonyldihydrochelerythrine; Anti-cancer; Dihydrochelerythrine; G-quadruplex; Suzuki coupling