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Synthesis of Biologically Active Molecules through Multicomponent Reactions
Open AccessArticle

Three-Component Reaction of Diamines with Triethyl Orthoformate and Diethyl Phosphite and Anti-Proliferative and Antiosteoporotic Activities of the Products

1
Department of Bioorganic Chemistry, Faculty of Chemistry, Wrocław University of Science and Technology, Wybrzeże Wyspiańskiego 27, 50-370 Wrocław, Poland
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Laboratory of Experimental Anticancer Therapy, Department of Experimental Oncology, Ludwik Hirszfeld Institute of Immunology and Experimental Therapy Polish Academy of Sciences, Rudolfa Weigla 12, 53-114 Wrocław, Poland
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Department of Surgery, The Faculty of Veterinary Medicine, Wrocław University of Environmental and Life Sciences, Norwida 31, 50-375 Wrocław, Poland
4
Division of Histology and Embryology, Department of Animal Physiology and Biostructure, The Faculty of Veterinary Medicine, Wrocław University of Environmental and Life Sciences, Norwida 31, 50-375 Wrocław, Poland
*
Author to whom correspondence should be addressed.
Academic Editors: Gian Cesare Tron, Tracey Pirali and Mariateresa Giustiniano
Molecules 2020, 25(6), 1424; https://doi.org/10.3390/molecules25061424
Received: 5 March 2020 / Revised: 14 March 2020 / Accepted: 18 March 2020 / Published: 20 March 2020
A three-component reaction between diamines (diaminobenzenes, diaminocyclohexanes, and piperazines), triethyl orthoformate, and diethyl phosphite was studied in some detail. In the case of 1,3- and 1,4-diamines and piperazines, products of the substitution of two amino moieties—the corresponding tetraphosphonic acids—were obtained. In the cases of 1,2-diaminobenzene, 1,2-diaminocyclohexanes and 1,2-diaminocyclohexenes, only one amino group reacted. This is most likely the result of the formation of hydrogen bonding between the phosphonate oxygen and a hydrogen of the adjacent amino group, which caused a decrease in the reactivity of the amino group. Most of the obtained compounds inhibited the proliferation of RAW 264.7 macrophages, PC-3 human prostate cancer cells, and MCF-7 human breast cancer cells, with 1, trans-7, and 16 showing broad nonspecific activity, which makes these compounds especially interesting in the context of anti-osteolytic treatment and the blocking of interactions and mutual activation of osteoclasts and tumor metastatic cells. These compounds exhibit similar activity to zoledronic acid and higher activity than incadronic acid, which were used as controls. However, studies of sheep with induced osteoporosis carried out with compound trans-7 did not support this assumption. View Full-Text
Keywords: bisphosphonic acids; synthesis of C-P bond; multicomponent reactions; P-containing drugs; anti-proliferative activity; osteoclasts; in vivo activity bisphosphonic acids; synthesis of C-P bond; multicomponent reactions; P-containing drugs; anti-proliferative activity; osteoclasts; in vivo activity
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Petruczynik, P.; Kafarski, P.; Psurski, M.; Wietrzyk, J.; Kiełbowicz, Z.; Kuryszko, J.; Chmielewska, E. Three-Component Reaction of Diamines with Triethyl Orthoformate and Diethyl Phosphite and Anti-Proliferative and Antiosteoporotic Activities of the Products. Molecules 2020, 25, 1424.

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