Scaffold Hopping and Structural Modification of NSC 663284: Discovery of Potent (Non)Halogenated Aminobenzoquinones

Nilüfer Bayrak; Belgin Sever; Halilibrahim Ciftci; Masami Otsuka; Mikako Fujita; Amaç Fatih TuYuN

doi:10.3390/biomedicines12010050

Scaffold Hopping and Structural Modification of NSC 663284: Discovery of Potent (Non)Halogenated Aminobenzoquinones

Biomedicines. 2023 Dec 24;12(1):50. doi: 10.3390/biomedicines12010050.

Authors

Nilüfer Bayrak¹, Belgin Sever^{2

3}, Halilibrahim Ciftci^{3

4

5}, Masami Otsuka^{3

4}, Mikako Fujita³, Amaç Fatih TuYuN¹

Affiliations

¹ Department of Chemistry, Faculty of Science, Istanbul University, Fatih, İstanbul 34126, Turkey.
² Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Anadolu University, Eskisehir 26470, Turkey.
³ Medicinal and Biological Chemistry Science Farm Joint Research Laboratory, Faculty of Life Sciences, Kumamoto University, Kumamoto 862-0973, Japan.
⁴ Department of Drug Discovery, Science Farm Ltd., Kumamoto 862-0976, Japan.
⁵ Department of Molecular Biology and Genetics, Koc University, Istanbul 34450, Turkey.

Abstract

The development of new anticancer drugs is still ongoing as a solution to the unsatisfactory results obtained by chemotherapy patients. Our previous studies on natural product-based anticancer agents led us to synthesize a new series of Plastoquinone (PQ) analogs and study their anticancer effects. Four members of PQ analogs (PQ1-4) were designed based on the scaffold hopping strategy; the design was later completed with structural modification. The obtained PQ analogs were synthesized and biologically evaluated against different cancer genotypes according to NCI-60 screening in vitro. According to the NCI results, bromo and iodo-substituted PQ analogs (PQ2 and PQ3) showed remarkable anticancer activities with a wide-spectrum profile. Among the two selected analogs (PQ2 and PQ3), PQ2 showed promising anticancer activity, in particular against leukemia cell lines, at both single- and five-dose NCI screenings. This compound was also detected by MTT assay to reveal significant selectivity between Jurkat cells and PBMC (healthy) compared to imatinib. Further in silico studies indicated that PQ2 was able to occupy the ATP-binding cleft of Abl TK, one of the main targets of leukemia, through key interactions similar to dasatinib and imatinib. PQ2 is also bound to the minor groove of the double helix of DNA. Based on computational pharmacokinetic studies, PQ2 possessed a remarkable drug-like profile, making it a potential anti-leukemia drug candidate for future studies.

Keywords: ADME; Abl TK; DNA; NSC 663284; anticancer activity; leukemia; molecular docking; quinones; scaffold hopping.

Grants and funding

This work was financially supported by the Scientific Research Projects Coordination Unit of Istanbul University (Project numbers: FBG-2022-38594) for supplying the equipment and materials.