Synthesis of new 13-diphenylalkyl analogues of berberine and elucidation of their base pair specificity and energetics of DNA binding

Abstract

A series of 13-diphenylalkyl berberine derivatives were designed and synthesized, and their base specificity and energetics of DNA binding were evaluated using one natural and two synthetic DNA polynucleotides.Biophysical evaluation demonstrated that the addition of the diphenylalkyl chain at the 13-position of berberine significantly improved the binding ability to DNA. The binding clearly revealed the high preference of the analogues to the alternating AT sequences compared to the alternating GC sequences.The binding affinity was enhanced with the increase in chain length up to a critical length of (CH 2 ) 3 in all the cases, after which the binding affinity decreased. Analogue BR4 had the best affinity for DNA, which corresponds to a length of (CH 2 ) 3 . The results also suggested the adenine-thymine (AT) base specificity of these berberine analogues and that the length of the side chain at the 13-position of the isoquinoline chromophore is critical in modulating the binding affinity. Scheme 1 Synthesis of (a) 13-diphenylmethylberberine (BR1): (i) NaBH 4 , Py, rt, 1 h; (ii) Ph 2 CHBr, CH 3 CN, NaI, 90 C, 12 h, then (iii) NaBH 4 , EtOH, 0 C to rt, 12 h; (iv) N-chlorosuccinimide, CHCl 3 , rt, 12 h; and (b) higher 13-diphenylalkylberberine (BR2-BR6): (v) Ph 2 CH(CH 2 ) 0-4 CHO, 80% aq. EtOH, AcOH, 85 C, 6 h, then (vi) 2 M HCl, rt, 2 h.

Recognition of human telomeric G‐quadruplex DNA by berberine analogs: effect of substitution at the 9 and 13 positions of the isoquinoline moiety

“…The isoquinoline alkaloids constitute a novel class of potential therapeutics owing to their wide range of pharmacological activities. As berberine is an important alkaloid of this group with potential anticancer activity, many studies on its derivatives are currently in progress in several laboratories to enhance its efficacy (Basu et al ., ; Liu et al ., ; Endoh et al ., ; Lo et al ., ; Marverti et al ., ; Pierpaoli et al ., ; Zhang et al ., ; Bhowmik et al ., ; Ortiz et al ., ). Various 9 and 13‐substituted berberine derivatives have been shown to induce G‐quadruplex formation and inhibit telomerase activity (Franceschin et al ., ; Gornall et al ., ; Ma et al ., ; Gornall et al ., ).…”

Solution and Solid‐State Analysis of Binding of 13‐Substituted Berberine Analogues to Human Telomeric G‐quadruplexes

“…It is well known that aromatic interactions are ubiquitous in nature and that their geometry plays acentral role in the molecular interaction with biological macromolecules. [15] Previous studies dealing with the elucidation of both dsDNA and RNA interaction modes of these structurally new derivatives (Scheme 1) [16][17][18][19] provided evidence of the contribution of the (di)phenylalkyl appendage to form stronger complexes with nucleic acids than BER.…”

Antitumor activity of NAX060: A novel semisynthetic berberine derivative in breast cancer cells

“…However, issues related with BBR poor absorption and bioavailability limit its biological effect . New compounds obtained by chemical manipulation of the plant alkaloid berberine provide a source of promising chemo‐therapeutic or chemo‐preventive agents, as shown by relevant scientific evidences .…”

“…However, evidence of poor bioavailability and toxicity represents relevant limits for the BBR biological effects in vivo . Different delivery systems and synthetic approaches have been developed to overcome these critical issues .…”