2. Academic Validation
  3. Artemisinin Derivatives with Antimelanoma Activity Show Inhibitory Effect against Human DNA Topoisomerase 1

Artemisinin Derivatives with Antimelanoma Activity Show Inhibitory Effect against Human DNA Topoisomerase 1

  • ACS Med Chem Lett. 2020 Apr 10;11(5):1035-1040. doi: 10.1021/acsmedchemlett.0c00131.
Lorenzo Botta 1,  Silvia Filippi 1,  Claudio Zippilli 1,  Silvia Cesarini 1,  Bruno Mattia Bizzarri 1,  Angela Cirigliano 2,  Teresa Rinaldi 3,  Alessandro Paiardini 4,  Diego Fiorucci 5,  Raffaele Saladino 1,  Rodolfo Negri 3,  Pietro Benedetti 6
Affiliations

Affiliations

  • 1 Department of Ecological and Biological Sciences, University of Tuscia, via S. C. De Lellis 44, 01100 Viterbo, Italy.
  • 2 Istituto di Biologia e Patologia Molecolari, CNR Piazzale Aldo Moro 5, 00185 Rome, Italy.
  • 3 Sapienza University of Rome, Department of Biology and Biotechnology, Piazzale Aldo Moro 5, 00185 Rome, Italy.
  • 4 Department of Biochemical Sciences "A. Rossi Fanelli", Sapienza University of Rome, Piazzale Aldo Moro 5, 00185 Rome, Italy.
  • 5 Department of Biotechnology, Chemistry and Pharmacy, University of Siena, Via A. Moro 2, 53100 Siena, Italy.
  • 6 Dipartimento di Biologia, Università di Padova Distaccato presso il "Centro Linceo Beniamino Segre" Accademia Nazionale dei Lincei, Palazzo Corsini, Via della Lungara 10, 00165 Rome, Italy.
PMID: 32435422 DOI: 10.1021/acsmedchemlett.0c00131
Abstract

Artesunic acid and artemisinin are natural substances with promiscuous Anticancer activity against different types of Cancer cell lines. The mechanism of action of these compounds is associated with the formation of reactive radical species by cleavage of the sesquiterpene pharmacophore endoperoxide bridge. Here we suggested Topoisomerase 1 as a possible molecular target for the improvement of the Anticancer activity of these compounds. In this context, we report that novel hybrid and dimer derivatives of artesunic acid and artemisinin, bearing camptothecin and SN38 as side-chain biological effectors, can inhibit growth of yeast cells overexpressing human Topoisomerase 1 and its enzymatic activity in vitro. These derivatives showed also Anticancer activity in melanoma cell lines higher than camptothecin and paclitaxel. In silico molecular docking calculations highlighted a common binding mode for the novel derivatives, with the sesquiterpene lactone scaffold being located near the traditional recognition site for camptothecin, while the bioactive side-chain effector laid in the camptothecin cleft.

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