The Synthesis of Nonsymmetric α‐hydroxy‐ethylidenebisphosphonic Derivatives by the Pudovik Reaction, Their Reactions, and Cytotoxic Activity

Nonsymmetric α-hydroxy-ethylidenebisphosphonates (HEBPs) are synthesized by the Pudovik reaction of dialkyl α-oxo-ethylphosphonates and P-reagents (such as dialkyl phosphites, alkyl phenyl-H-phosphinates or diarylphosphine oxides). In the presence of 40% diethylamine, the primary adducts rearrange to the corresponding phosphonoyl-phosphonate and phosphoryl-phosphinate. Acylation of the HEBPs leads to the respective derivatives. Significant cytotoxic effects are observed on multiple myeloma cell lines.

Abstract

Nonsymmetric α-hydroxy-ethylidenebisphosphonic (HEBP) derivatives were synthesized by the Pudovik reaction of dialkyl α-oxo-ethylphosphonates (DAOEPs) and P-reagents, such as dialkyl phosphites, alkyl phenyl-H-phosphinates (APHPs) and diarylphosphine oxides to make available a new family of compounds with two different P-functions. Performing the addition of APHPs to DAOEPs in the presence of 40% of the diethylamine catalyst, the primary adducts rearranged to the mixture of the corresponding phosphonoyl-phosphonate and phosphoryl-phosphinate. Acylation of the HEBPs led to the formation of the respective acylated derivatives. A part of the new P-compounds was subjected to cytotoxic screening on myeloma and metastatic cell lines. Among these, two derivatives, dibutyl 1-(butyl-phenylphosphinoyl)-1-hydroxy-ethylphosphonate 4a and tetrabutyl α-acetyloxy-ethylidenebisphosphonate 8c, demonstrated the strongest antiproliferative effects on the A2058 (metastatic melanoma) and U266 (multiple myeloma) cell lines, highlighting their potential as promising candidates for further therapeutic development. The bisphosphonic derivatives 4a and 8c reduced the viability of U266 cells by 94% and 91%, respectively

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