TY - JOUR
T1 - Sulfonamide-based 4-anilinoquinoline derivatives as novel dual Aurora kinase (AURKA/B) inhibitors
T2 - Synthesis, biological evaluation and in silico insights
AU - Al-Sanea, Mohammad M.
AU - Elkamhawy, Ahmed
AU - Paik, Sora
AU - Lee, Kyeong
AU - El Kerdawy, Ahmed M.
AU - Syed Nasir Abbas, Bukhari
AU - Joo Roh, Eun
AU - Eldehna, Wagdy M.
AU - Elshemy, Heba A.H.
AU - Bakr, Rania B.
AU - Ali Farahat, Ibrahim
AU - Alzarea, Abdulaziz I.
AU - Alzarea, Sami I.
AU - Alharbi, Khalid S.
AU - Abdelgawad, Mohamed A.
N1 - Publisher Copyright:
© 2020 Elsevier Ltd
PY - 2020/7/1
Y1 - 2020/7/1
N2 - Aurora kinases (AURKs) were identified as promising druggable targets for targeted cancer therapy. Aiming at the development of novel chemotype of dual AURKA/B inhibitors, herein we report the design and synthesis of three series of 4-anilinoquinoline derivatives bearing a sulfonamide moiety (5a-d, 9a-d and 11a-d). The % inhibition of AURKA/B was determined for all target quinolines, then compounds showed more than 50% inhibition on either of the enzymes, were evaluated further for their IC50 on the corresponding enzyme. In particular, compound 9d displayed potent AURKA/B inhibitory activities with IC50 of 0.93 and 0.09 µM, respectively. Also, 9d emerged as the most efficient anti-proliferative analogue in the US-NCI anticancer assay toward the NCI 60 cell lines panel, with broad spectrum activity against different cell lines from diverse cancer subpanels. Docking studies, confirmed that, the sulfonamide SO2 oxygen was involved in a hydrogen bond with Lys162 and Lys122 in AURKA and AURKB, respectively, whereas, the sulfonamide NH could catch hydrogen bond interaction with the surrounding amino acid residues Lys141, Glu260, and Asn261 in AURKA and Lys101, Glu177, and Asp234 in AURKB. Furthermore, N1 nitrogen of the quinoline scaffold formed an essential hydrogen bond with the hinge region key amino acids Ala213 and Ala173 in AURKA and AURKB, respectively.
AB - Aurora kinases (AURKs) were identified as promising druggable targets for targeted cancer therapy. Aiming at the development of novel chemotype of dual AURKA/B inhibitors, herein we report the design and synthesis of three series of 4-anilinoquinoline derivatives bearing a sulfonamide moiety (5a-d, 9a-d and 11a-d). The % inhibition of AURKA/B was determined for all target quinolines, then compounds showed more than 50% inhibition on either of the enzymes, were evaluated further for their IC50 on the corresponding enzyme. In particular, compound 9d displayed potent AURKA/B inhibitory activities with IC50 of 0.93 and 0.09 µM, respectively. Also, 9d emerged as the most efficient anti-proliferative analogue in the US-NCI anticancer assay toward the NCI 60 cell lines panel, with broad spectrum activity against different cell lines from diverse cancer subpanels. Docking studies, confirmed that, the sulfonamide SO2 oxygen was involved in a hydrogen bond with Lys162 and Lys122 in AURKA and AURKB, respectively, whereas, the sulfonamide NH could catch hydrogen bond interaction with the surrounding amino acid residues Lys141, Glu260, and Asn261 in AURKA and Lys101, Glu177, and Asp234 in AURKB. Furthermore, N1 nitrogen of the quinoline scaffold formed an essential hydrogen bond with the hinge region key amino acids Ala213 and Ala173 in AURKA and AURKB, respectively.
KW - 4-Anilinoquinoline
KW - Anticancer
KW - Aurora Kinase A and B
KW - Molecular docking
KW - Synthesis
UR - http://www.scopus.com/inward/record.url?scp=85084207832&partnerID=8YFLogxK
U2 - 10.1016/j.bmc.2020.115525
DO - 10.1016/j.bmc.2020.115525
M3 - Article
C2 - 32371117
AN - SCOPUS:85084207832
SN - 0968-0896
VL - 28
JO - Bioorganic and Medicinal Chemistry
JF - Bioorganic and Medicinal Chemistry
IS - 13
M1 - 115525
ER -