Exploring the physicochemical and antiproliferative properties of biaryl-linked [13]-macrodilactones |
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| Institution: | 1. Department of Chemistry, University of Connecticut, 55 N. Eagleville Road U3060, Storrs, CT, United States;2. Department of Pharmaceutical Sciences, School of Pharmacy, 69 N. Eagleville Road U3092, University of Connecticut, Storrs, CT 06269, United States;1. Instituto de Investigação do Medicamento (iMed.ULisboa), Faculdade de Farmácia, Universidade de Lisboa Av. Prof. Gama Pinto, 1649-003 Lisboa, Portugal;2. Charité Campus Mitte, Institute of Pathology, Berlin, Germany;1. Departamento de Química Inorgánica, Facultad de Química, Pontificia Universidad Católica de Chile, Casilla 306, Santiago 22, Chile;2. Departamento de Farmacia, Facultad de Química, Pontificia Universidad Católica de Chile, Casilla 306, Santiago 22, Chile;1. Research Center for Bio-microsensing Technology, 1-1 Sensui-cho, Tobata-ku, Kitakyushu-shi, Fukuoka 804-8550, Japan;2. Department of Applied Chemistry, Kyushu Institute of Technology, 1-1 Sensui-cho, Tobata-ku, Kitakyushu-shi, Fukuoka 804-8550, Japan;3. Laboratory of Bioanalytical Chemistry, Faculty of Chemistry, A. Mickiewicz University, Umultowska 89b, 61-614 Poznań, Poland;1. Departamento de Química Farmacéutica y Orgánica, Facultad de Farmacia, Universidad de Granada, c/ Campus de Cartuja s/n, 18071 Granada, Spain;2. Instituto de Parasitología y Biomedicina “López-Neyra”, IPBLN-CSIC, Parque Tecnológico de Ciencias de la Salud, Avda. del Conocimiento s/n, 18016 Armilla, Granada, Spain;1. Medicinal Chemistry Research Laboratories, R&D Division, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan;2. Specialty Medicine Research Laboratories, R&D Division, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan;3. Intellectual Property Department, Global Brand Strategy Division, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan;1. Istituto di Biochimica delle Proteine – CNR, Via P. Castellino 111, 80131 Napoli, Italy;2. Università degli Studi di Firenze, Laboratorio di Chimica Bioinorganica, Rm. 188, Via della Lastruccia 3, I-50019 Sesto Fiorentino (Firenze), Italy;3. Department of Chemistry, College of Science, King Saud University, PO Box 2455, Riyadh 11451, Saudi Arabia;4. Università degli Studi di Firenze, Polo Scientifico, Dipartimento NEIROFABA;Sezione di Scienze Farmaceutiche e Nutraceutiche, Via Ugo Schiff 6, 50019 Sesto Fiorentino (Firenze), Italy |
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| Abstract: | A macrocyclic motif fosters productive protein-small molecule interactions. There are numerous examples of both natural product and designed, synthetic macrocycles that modulate the immune system, slow microbial infection, or kill eukaryotic cells. Reported here are the synthesis, physicochemical characterization, and antiproliferative activity of a group of 13]-macrodilactones decorated with a pendant biaryl moiety. Biaryl analogs were prepared by Suzuki reactions conducted on a common intermediate that contained a bromophenyl unit alpha to one of the carbonyls of the 13]-macrodilactone. Principal component analysis placed the new compounds in physicochemical context relative to a variety of pharmaceuticals and natural products. Modest inhibition of proliferation was observed in ASZ cells, a murine basal cell carcinoma line. This work underscores the value of an approach toward the identification of bioactive compounds that places the evaluation of physicochemical parameters early in the search process. |
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| Keywords: | Macrocycle Principal component analysis Synthesis Antiproliferative |
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