title: Identification and Synthesis of Mycalol Analogues with Improved Potency against Anaplastic Thyroid Carcinoma Cell Lines.
abstract: The marine metabolite mycalol (1) has a specific inhibitory activity on cells of anaplastic thyroid carcinoma (ATC), a very aggressive and rare cancer that does not have effective conventional therapy. In this study, we describe six new related analogues (2-7) that differ in the length of the terminal alkyl residue and the presence of acetate or 3S-hydroxybutyrate (3S)-3HB as a substituent at C-19. Despite the structural analogies, some of the new members were significantly more cytotoxic than 1 on cell lines derived from human ATC. Structures inclusive of the 2'R,3R,4S,7R,8S,19R absolute configuration were assigned to 2-7 on the basis of detailed spectroscopic analysis, synthesis of different isomers, and application of ECD and Mosher's methods. This work led to the identification of mycalol-578 (3) as the most potent analogue, with an IC50of 2.3 μM on FRO cells.
authors.affiliation: Istituto di Chimica Biomolecolare, Bio-Organic Chemistry Unit, Consiglio Nazionale delle Ricerche , Via Campi Flegrei 34, 80078, Pozzuoli, Naples, Italy.
authors.forename: Adele
authors.initials: A
authors.lastname: Cutignano
authors.affiliation: Division of Organic Chemistry, CSIR-National Chemical Laboratory , Dr. Homi Bhabha Road, Pune, 411008, India.
authors.forename: B
authors.initials: B
authors.lastname: Seetharamsingh
authors.affiliation: Istituto per l'Endocrinologia e l'Oncologia Sperimentale, Consiglio Nazionale delle Ricerche , Via Pansini 5, 80131, Napoli, Italy.|Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Universita' degli Studi di Napoli "Federico II" , Via Pansini 5, 80131, Napoli, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: D'Angelo
authors.affiliation: Istituto di Chimica Biomolecolare, Bio-Organic Chemistry Unit, Consiglio Nazionale delle Ricerche , Via Campi Flegrei 34, 80078, Pozzuoli, Naples, Italy.
authors.forename: Genoveffa
authors.initials: G
authors.lastname: Nuzzo
authors.affiliation: Division of Organic Chemistry, CSIR-National Chemical Laboratory , Dr. Homi Bhabha Road, Pune, 411008, India.
authors.forename: Pankaj V
authors.initials: PV
authors.lastname: Khairnar
authors.affiliation: Istituto per l'Endocrinologia e l'Oncologia Sperimentale, Consiglio Nazionale delle Ricerche , Via Pansini 5, 80131, Napoli, Italy.|Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Universita' degli Studi di Napoli "Federico II" , Via Pansini 5, 80131, Napoli, Italy.
authors.forename: Alfredo
authors.initials: A
authors.lastname: Fusco
authors.affiliation: Division of Organic Chemistry, CSIR-National Chemical Laboratory , Dr. Homi Bhabha Road, Pune, 411008, India.
authors.forename: D Srinivasa
authors.identifier: 0000-0003-3270-315X
authors.initials: DS
authors.lastname: Reddy
authors.affiliation: Istituto di Chimica Biomolecolare, Bio-Organic Chemistry Unit, Consiglio Nazionale delle Ricerche , Via Campi Flegrei 34, 80078, Pozzuoli, Naples, Italy.
authors.forename: Angelo
authors.identifier: 0000-0002-5453-461X
authors.initials: A
authors.lastname: Fontana
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D005233:Fatty Alcohols / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D015394:Molecular Structure; D019906:Nuclear Magnetic Resonance, Biomolecular; D011161:Porifera / Q000737:chemistry; D065646:Thyroid Carcinoma, Anaplastic / Q000188:drug therapy*
chemical_list: D000970:Antineoplastic Agents; D005233:Fatty Alcohols; C586897:mycalol