2. Academic Validation
  3. Mono- and bis-pyrazolophthalazines: Design, synthesis, cytotoxic activity, DNA/HSA binding and molecular docking studies

Mono- and bis-pyrazolophthalazines: Design, synthesis, cytotoxic activity, DNA/HSA binding and molecular docking studies

  • Bioorg Med Chem. 2021 Jan 15:30:115944. doi: 10.1016/j.bmc.2020.115944.
Mahdia Hamidinasab 1,  Alieh Ameri 2,  Azadeh Hekmat 3,  Hamid Forootanfar 4,  Tohid Mortezazadeh 5,  Mohammad Ali Bodaghifard 1,  Fariba Peytam 6,  Rezvan Esmaeili 7,  Alireza Foroumadi 8,  Mohammad Sharifzadeh 9,  Akbar Mobinikhaledi 10,  Mehdi Khoobi 11
Affiliations

Affiliations

  • 1 Department of Chemistry, Faculty of Science, Arak University, Arak 38156-88138, Iran; Institute of Nanosciences and Nanotechnology, Arak University, Arak 38156-88138, Iran.
  • 2 Department of Medicinal Chemistry, Faculty of Pharmacy, Kerman University of Medical Sciences, Kerman, Iran.
  • 3 Department of Biology, Science and Research Branch, Islamic Azad University, Tehran, Iran.
  • 4 Department of Pharmaceutical Biotechnology, Faculty of Pharmacy, Kerman University of Medical Sciences, Kerman, Iran; Pharmaceutical Sciences and Cosmetic Products Research Center, Kerman University of Medical Sciences, Kerman, Iran.
  • 5 Department of Medical Physics, School of Medicine, Tabriz University of Medical Science, Tabriz, Iran.
  • 6 Department of Medicinal Chemistry, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran.
  • 7 Genetics Department, Breast Cancer Research Center, Motamed Cancer Institute, ACECR, Tehran, Iran.
  • 8 Department of Medicinal Chemistry, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran; Drug Design and Development Research Center, The Institute of Pharmaceutical Sciences (TIPS), Tehran University of Medical Sciences, Tehran, Iran.
  • 9 Department of Pharmacology and Toxicology, Faculty of Pharmacy, Toxicology and Poisoning Research Centre, Tehran University of Medical Sciences, Tehran, Iran.
  • 10 Department of Chemistry, Faculty of Science, Arak University, Arak 38156-88138, Iran; Institute of Nanosciences and Nanotechnology, Arak University, Arak 38156-88138, Iran. Electronic address: akbar_mobini@yahoo.com.
  • 11 Department of Medicinal Chemistry, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran; Biomaterials Group, Pharmaceutical Sciences Research Center, The Institute of Pharmaceutical Sciences (TIPS), Tehran University of Medical Sciences, Tehran 1417614411, Iran. Electronic address: Mehdi.khoobi@gmail.com.
PMID: 33352388 DOI: 10.1016/j.bmc.2020.115944
Abstract

In an attempt to find new potent cytotoxic compounds, several mono- and bis-pyrazolophthalazines 4a-m and 6a-h were synthesized through an efficient, one-pot, three- and pseudo five-component synthetic approach. All derivatives were evaluated for their in vitro cytotoxic activities against four human Cancer cell lines of A549, HepG2, MCF-7, and HT29. Compound 4e showed low toxicity against normal cell lines (MRC-5 and MCF 10A, IC50 > 200 µM) and excellent cytotoxic activity against A549 cell line with IC50 value of 1.25 ± 0.19 µM, which was 1.8 times more potent than doxorubicin (IC50 = 2.31 ± 0.13 µM). In addition, compound 6c exhibited remarkable cytotoxic activity against A549 and MCF-7 cell lines (IC50 = 1.35 ± 0.12 and 0.49 ± 0.01 µM, respectively), more than two-fold higher than that of doxorubicin. The binding properties of the best active mono- and bis-pyrazolophthalazine (4e and 6c) with HSA and DNA were fully evaluated by various techniques including UV-Vis absorption, circular dichroism (CD), Zeta potential and dynamic light scattering analyses indicating interaction of the compounds with the secondary structure of HSA and significant change of DNA conformation, presumably via a groove binding mechanism. Additionally, molecular docking and site-selective binding studies confirmed the fundamental interaction of compounds 4e and 6c with base pairs of DNA. Compounds 4e and 6c showed promising features to be considered as potential lead structures for further studies in Cancer therapy.

Keywords

Anticancer; Cytotoxic; Human serum albumins (HSA); Pyrazolophthalazines; Transport proteins.

Figures