Synthesis of IB-01212 by multiple N-methylations of peptide bonds |
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| Institution: | 1. Institute for Research in Molecular Medicine, Universiti Sains Malaysia, Minden, 11800 Penang, Malaysia;2. School of Science, Monash University Malaysia Campus, Jalan Lagoon Selatan, Bandar Sunway, 47500 Selangor, Malaysia;3. Department of Pharmacology, School of Pharmaceutical Sciences, Universiti Sains Malaysia, Minden, 11800 Penang, Malaysia;4. Department of Organic Chemistry, School of Chemical Sciences, Universiti Sains Malaysia, Minden, 11800 Penang, Malaysia;1. Drug Design and Synthesis Section, Chemical Biology Research Branch, National Institute on Drug Abuse and the National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Department of Health and Human Services, 5625 Fishers Lane, Room 4N03, Bethesda, MD 20892-9415, USA;2. Clinical Psychopharmacology Section, Chemical Biology Research Branch, National Institute on Drug Abuse, Addiction Research Center, National Institutes of Health, Department of Health and Human Services, Baltimore, MD 21224, USA;3. Laboratory for the Structure of Matter, Naval Research Laboratory, Washington, DC 20375, USA;1. Departamentos de Fisiología y Bioquímica, Escuela Superior de Medicina, Instituto Politécnico Nacional, Plan de San Luis y Díaz Mirón, México, D.F. C.P. 11340, Mexico;2. Sección de Estudios de Posgrado e Investigación, Escuela Superior de Medicina, Instituto Politécnico Nacional, Plan de San Luis y Díaz Mirón, 11340, Mexico;3. Departamento de Fisiología, Biofísica y Neurociencias, Centro de Investigación y de Estudios Avanzados del I.P.N., Av. IPN 2508, 07360 Mexico, D.F., Mexico;4. Unidad Profesional Interdisciplinaria de Biotecnología, Instituto Politécnico Nacional, Avenida Acueducto s/n, Barrio La Laguna Ticomán, 07340, Mexico;1. Institute of Bioorganic Chemistry, Polish Academy of Sciences, Z. Noskowskiego 12/14, 61-704 Poznań, Poland;2. Faculty of Chemistry, Adam Mickiewicz University in Poznań, Umultowska 89 b, 61-614 Poznań, Poland;1. M. M. Shemyakin–Yu. A. Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, 117997 Moscow, Russian Federation;2. N. I. Pirogov Russian National Research Medical University, 117997 Moscow, Russian Federation;3. Institute of Fundamental Biology and Biotechnology, Siberian Federal University, 660041 Krasnoyarsk, Russian Federation;4. Institute of Biophysics, Siberian Branch of the Russian Academy of Sciences, 660036 Krasnoyarsk, Russian Federation;5. ‘Drugs Technology’ Ltd., 141400 Khimki, Moscow Region, Russian Federation |
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| Abstract: | There are many natural peptides with multiple N-methylamino acids that exhibit potent attractive biological activities. N-methylation of a peptide bond(s) is also one of the standard approaches in medicinal chemistry of bioactive peptides, to improve the potency and physicochemical properties, especially membrane permeability. In this study, we investigated a facile synthesis process of N-methylated peptides via simultaneous N-methylation of several peptide bonds in the presence of peptide bonds that were not to be methylated. As a model study, we investigated the synthesis of the antiproliferative depsipeptide, IB-01212. We used a pseudoproline to protect the non-methylated peptide bond during a simultaneous N-methylation with MeI–Ag2O. Using further manipulations including a dimerization/cyclization process, IB-01212 and its derivatives were successfully synthesized. A preliminary structure–activity relationship study demonstrated that the symmetric structure contributed to the potent cytotoxic activity of IB-01212. |
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| Keywords: | Depsipeptide Macrolactonization N-methylation |
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