Design, Synthesis, and Evaluation of ω‐(Isothiocyanato)alkylphosphinates and Phosphine Oxides as Antiproliferative Agents

Abstract

A series of 21 novel, structurally diverse ω‐(isothiocyanato)alkylphosphinates and phosphine oxides (ITCs) were designed and synthesized in moderate to good yields. The synthesized compounds were evaluated for in vitro antiproliferative activity using LoVo and LoVo/DX cancer cell lines. The biological activity of the synthesized compounds was higher than that of natural isothiocyanates such as benzyl isothiocyanate or sulforaphane. The antiproliferative activity of selected ITCs was also tested on selected cancer cell lines: A549, MESSA and MESSA/DX‐5, HL60 and HL60MX2, BALB/3T3, and 4T1. These compounds were assessed for their mechanism of action as inducers of cell‐cycle arrest and apoptosis. Ethyl (6‐isothiocyanatohexyl)(phenyl)phosphinate (71) was tested in vivo on the 4T1 cell line and demonstrated moderate antitumor activity, similar to that benzyl isothiocyanate and cyclophosphamide.

RASS‐Enabled S/P−C and S−N Bond Formation for DEL Synthesis

“…During the course of this study, it was also found that phosphinic chlorides are competent coupling partners for aryl iodides creating C−P linkages that are increasingly desired as pharmacophores (Figure A) . Notably, these cross‐coupling conditions are intolerant to water, making them incompatible with traditional DEL formats.…”

Reaction of 2‐Imino‐2H‐chromene‐3‐carboxamide with Phosphorus Isothiocyanates: First Synthesis of Novel Chromeno[2,3‐d]pyrimidinyl and Bis(chromeno[2,3‐d]pyrimidinyl)phosphines and Chromeno[2′,3′:4,5]pyrimido[2,1‐d][1,3,5,2]triazaphosphinine

“…Reaction of phenyl phosphorus halides with potassium thiocyanate can form chemically active phosphorus isothiocyanate in situ . These reagents can react with 2‐imino‐2 H ‐chromene‐3‐carboxamide ( 1 ), forming novel interesting phosphorus‐containing heterocycles.…”

Synthesis of Isothiocyanates Using DMT/NMM/TsO− as a New Desulfurization Reagent

“…Isothiocyanateshave many desirable characteristics, including primarily anti-proliferative properties [ 9 , 10 , 11 , 12 , 13 , 14 , 15 ]. Like naturally occurring isothiocyanates (e.g., sulforaphane [ 16 , 17 , 18 , 19 , 20 ] (SFN), phenethyl isothiocyanate [ 21 ] (PEITC), or benzyl isothiocyanate [ 22 ] (BITC)), their synthetically modified analogs with the structure of a phosphorus atom [ 23 , 24 ] or fluorine atom [ 25 , 26 ] also exhibit anti-proliferative activity. Natural as well as synthetic ITCs may additionally have anti-bacterial [ 27 , 28 , 29 , 30 ], anti-fungal [ 31 ], and anti-glioblastoma effects [ 32 ].…”