2. Academic Validation
  3. Structural-based design, synthesis, and antitumor activity of novel alloxazine analogues with potential selective kinase inhibition

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.
Waleed H Malki 1,  Ahmed M Gouda 2,  Hamdy E A Ali 3,  Rabaa Al-Rousan 4,  Doaa Samaha 5,  Ashraf N Abdalla 1,  Juan Bustamante 3,  Zakaria Y Abd Elmageed 3,  Hamed I Ali 6
Affiliations

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: alyismail@pharmacy.tamhsc.edu.
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.

Figures
嗨！很高兴为您提供帮助！

尊敬的 MCE 客户您好，
请您选择所在区域，我们将转接对应客服为您服务！

热门区域

A

B

C

F

G

H

J

L

N

Q

S

T

X

Y

Z

热 A B C F G H J L N Q S T X Y Z