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  3. Sulfonamide-based 4-anilinoquinoline derivatives as novel dual Aurora kinase (AURKA/B) inhibitors: Synthesis, biological evaluation and in silico insights

Sulfonamide-based 4-anilinoquinoline derivatives as novel dual Aurora kinase (AURKA/B) inhibitors: Synthesis, biological evaluation and in silico insights

  • Bioorg Med Chem. 2020 Jul 1;28(13):115525. doi: 10.1016/j.bmc.2020.115525.
Mohammad M Al-Sanea 1,  Ahmed Elkamhawy 2,  Sora Paik 3,  Kyeong Lee 4,  Ahmed M El Kerdawy 5,  Bukhari Syed Nasir Abbas 6,  Eun Joo Roh 7,  Wagdy M Eldehna 8,  Heba A H Elshemy 9,  Rania B Bakr 10,  Ibrahim Ali Farahat 11,  Abdulaziz I Alzarea 12,  Sami I Alzarea 13,  Khalid S Alharbi 13,  Mohamed A Abdelgawad 14
Affiliations

Affiliations

  • 1 Department of Pharmaceutical Chemistry, College of Pharmacy, Jouf University, Sakaka, Aljouf 72341, Saudi Arabia. Electronic address: mmalsanea@ju.edu.sa.
  • 2 College of Pharmacy, Dongguk University-Seoul, Goyang 10326, Republic of Korea; Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt. Electronic address: a_elkamhawy@mans.edu.eg.
  • 3 Chemical Kinomics Research Center, Korea Institute of Science and Technology (KIST), Seoul 02792, Republic of Korea.
  • 4 College of Pharmacy, Dongguk University-Seoul, Goyang 10326, Republic of Korea.
  • 5 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Cairo University, Kasr El-Aini Street, Cairo P.O. Box 11562, Egypt; Department of Pharmaceutical Chemistry, Faculty of Pharmacy, New Giza University, New giza, km 22, Cairo-Alexandria Desert Road, Cairo, Egypt. Electronic address: ahmed.elkerdawy@cu.edu.eg.
  • 6 Department of Pharmaceutical Chemistry, College of Pharmacy, Jouf University, Sakaka, Aljouf 72341, Saudi Arabia.
  • 7 Chemical Kinomics Research Center, Korea Institute of Science and Technology (KIST), Seoul 02792, Republic of Korea; Division of Bio-Medical Science & Technology, KIST School, Korea University of Science and Technology, Seoul 02792, Republic of Korea.
  • 8 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh, Egypt.
  • 9 Department of Pharmaceutical Organic Chemistry, Beni-Suef University, Beni-Suef 62514, Egypt.
  • 10 Department of Pharmaceutical Chemistry, College of Pharmacy, Jouf University, Sakaka, Aljouf 72341, Saudi Arabia; Department of Pharmaceutical Organic Chemistry, Beni-Suef University, Beni-Suef 62514, Egypt.
  • 11 Department of Orthopedics and Traumatology, Faculty of Medicine, Mansoura University, Mansoura 35516, Egypt.
  • 12 Clinical Pharmacy Department, College of Pharmacy, Jouf University, Sakaka, Aljouf 72341, Saudi Arabia.
  • 13 Department of Pharmacology, College of Pharmacy, Jouf University, Sakaka, Aljouf 72341, Saudi Arabia.
  • 14 Department of Pharmaceutical Chemistry, College of Pharmacy, Jouf University, Sakaka, Aljouf 72341, Saudi Arabia; Department of Pharmaceutical Organic Chemistry, Beni-Suef University, Beni-Suef 62514, Egypt. Electronic address: mhmdgwd@ju.edu.sa.
PMID: 32371117 DOI: 10.1016/j.bmc.2020.115525
Abstract

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.

Keywords

4-Anilinoquinoline; Anticancer; Aurora Kinase A and B; Molecular docking; Synthesis.

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