Structural-based design, synthesis, and antitumor activity of novel alloxazine analogues with potential selective kinase inhibition

Waleed H Malki; Ahmed M Gouda; Hamdy E A Ali; Rabaa Al-Rousan; Doaa Samaha; Ashraf N Abdalla; Juan Bustamante; Zakaria Y Abd Elmageed; Hamed I Ali

doi:10.1016/j.ejmech.2018.04.029

Structural-based design, synthesis, and antitumor activity of novel alloxazine analogues with potential selective kinase inhibition

Eur J Med Chem. 2018 May 25:152:31-52. doi: 10.1016/j.ejmech.2018.04.029. Epub 2018 Apr 17.

Authors

Waleed H Malki¹, Ahmed M Gouda², Hamdy E A Ali³, Rabaa Al-Rousan⁴, Doaa Samaha⁵, Ashraf N Abdalla¹, Juan Bustamante³, Zakaria Y Abd Elmageed³, Hamed I Ali⁶

Affiliations

¹ Department of Pharmacology, College of Pharmacy, Umm Al-Qura University, KSA.
² Department of Pharmaceutical Chemistry, College of Pharmacy, Umm Al-Qura University, KSA; Department of Medicinal Chemistry, College of Pharmacy, Beni-Suef University, Beni-Suef 62514, Egypt.
³ Rangel College of Pharmacy, Health Science Center, Texas A&M University, Kingsville, TX 78363, United States.
⁴ The Ben and Maytee Fisch College of Pharmacy, The University of Texas at Tyler, Tyler, TX 75799, United States.
⁵ Institute of Chemistry, Humboldt-Universität zu Berlin, Brook-Taylor-Str. 2, Berlin 12489, Germany; Department of Pharmaceutical Chemistry, College of Pharmacy, Helwan University, Cairo 11795, Egypt.
⁶ Rangel College of Pharmacy, Health Science Center, Texas A&M University, Kingsville, TX 78363, United States; Department of Pharmaceutical Chemistry, College of Pharmacy, Helwan University, Cairo 11795, Egypt. Electronic address: [email protected].

PMID: 29684708
DOI: 10.1016/j.ejmech.2018.04.029

Abstract

Protein kinases are promising therapeutic targets for cancer therapy. Here, we applied multiple approaches to optimize the potency and selectivity of our reported alloxazine scaffold. Flexible moieties at position 2 of the hetero-tricyclic system were incorporated to fit into the ATP binding site and extend to the adjacent allosteric site and selectively inhibit protein kinases. This design led to potential selective inhibition of ABL1, CDK1/Cyclin A1, FAK, and SRC kinase by 30-59%. Cytotoxicity was improved by ∼50 times for the optimized lead (10b; IC₅₀ = 40 nM) against breast cancer (MCF-7) cells. Many compounds revealed potential cytotoxicity against ovarian (A2780) and colon carcinoma (HCT116) cells of ∼10-30 time improvement (IC₅₀ 5-17 nM). The results of the Annexin-V/PI apoptotic assay demonstrated that many compounds induced significantly early (89-146%) and a dramatically late (556-1180%) cell death in comparison to the vehicle control of MCF-7 cells. SAR indicated that 5-deazaalloxazines have a higher selectivity for Abl-1 and FAK kinases than alloxazines. The correlations between GoldScore fitness into FAK and SRC kinases and IC₅₀ against MCF-7 and A2780 cells were considerable (R²: 0.86-0.98).

Keywords: Alloxazine; Antitumor; Apoptosis; Docking; Kinase inhibitor.

MeSH terms

Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Apoptosis / drug effects
Cell Proliferation / drug effects
Dose-Response Relationship, Drug
Drug Design*
Drug Screening Assays, Antitumor
Flavins / chemical synthesis
Flavins / chemistry
Flavins / pharmacology*
Humans
MCF-7 Cells
Molecular Docking Simulation
Molecular Structure
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology*
Protein Kinases / metabolism*
Structure-Activity Relationship
Tumor Cells, Cultured

Substances

Antineoplastic Agents
Flavins
Protein Kinase Inhibitors
isoalloxazine
Protein Kinases