Design and synthesis of C3-pyrazole/chalcone-linked beta-carboline hybrids: antitopoisomerase I, DNA-interactive, and apoptosis-inducing anticancer agents.
A series of β-carboline hybrids bearing a substituted phenyl and a chalcone/(N-acetyl)-pyrazole moiety at the C1 and C3 positions, respectively, was designed, synthesized, and evaluated for anticancer activity. These new hybrid molecules showed significant cytotoxic activity, with IC50 values ranging from <2.0 μM to 80 μM, and the structure-activity relationships (SAR) associated with substitutions at positions 1 and 3 of these hybrids was clearly addressed. Further, induction of apoptosis was confirmed by Annexin V-FITC, Hoechst staining, and DNA fragmentation analysis. In addition, DNA photocleavage studies proved that two of the hybrids, (E)-1-(furan-2-yl)-3-(1-(4-(trifluoromethyl)phenyl)-9H-pyrido[3,4-b]indol-3-yl)prop-2-en-1-one (7 d) and 1-(3-(furan-2-yl)-5-(1-(4-(trifluoromethyl)phenyl)-9H-pyrido[3,4-b]indol-3-yl)-4,5-dihydro-1H-pyrazol-1-yl)ethanone (8 d) could effectively cleave pBR322 plasmid DNA upon irradiation with UV light. Active hybrid 8 d inhibited DNA topoisomerase I activity efficiently and preserved DNA in the supercoiled form. To further corroborate the biological activities, as well as to understand the nature of the interaction of these hybrids with DNA, spectroscopic studies were also performed. Unlike simple β-carboline alkaloids, the binding mode of these new hybrid molecules with DNA was not similar, and both biophysical as well as molecular docking studies speculated a combilexin-type of interaction with DNA. Further, an in silico study of these β-carboline hybrids revealed their drug-like properties.
Medicinal Chemistry & Pharmacology, CSIR-Indian Institute of Chemical Technology, Hyderabad 500 007 (India); Department of Medicinal Chemistry, National Institute of Pharmaceutical Education & Research (NIPER), Hyderabad 500 037 (India). ahmedkamal@iict.res.in.
Ahmed
A
Kamal
Vunnam
V
Srinivasulu
V Lakshma
VL
Nayak
Manda
M
Sathish
Nagula
N
Shankaraiah
Chandrakant
C
Bagul
N V Subba
NV
Reddy
Nandini
N
Rangaraj
Narayana
N
Nagesh
D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D002243:Carbolines / Q000138:chemical synthesis*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D047188:Chalcones / Q000737:chemistry*; D053837:DNA Cleavage / Q000187:drug effects; D004273:DNA, Neoplasm / Q000187:drug effects*; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D008958:Models, Molecular; D011720:Pyrazoles / Q000737:chemistry*; D059004:Topoisomerase I Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*
D000970:Antineoplastic Agents; D002243:Carbolines; D047188:Chalcones; D004273:DNA, Neoplasm; D011720:Pyrazoles; D059004:Topoisomerase I Inhibitors
DNA binding; DNA photocleavage; anticancer activity; beta-carboline hybrids; topoisomerase I inhibition