Novel silicon-containing drugs derived from the indomethacin scaffold: Synthesis, characterization and evaluation of biological activity

Abstract

Synthesis, spectroscopic characterization and in vitro pharmacological and cancer cell growth inhibitory activity studies of new silicon-containing compounds based on the indomethacin scaffold are now reported. Amidation of the indomethacin carboxylate group using amino-functional silanes generated a series of novel lipophilic derivatives of indomethacin. The pharmacological activity of these derivatives tested against human recombinant cyclooxygenase-1 and 2 demonstrated that the silicon-containing derivatives are cyclooxygenase-2 (COX-2) selective. The silicon-containing amides of indomethacin demonstrated in vitro growth inhibitory activity against human MiaPaCa-2 pancreatic carcinoma cells at low μM concentrations. The 3a and 3c derivatives exhibited the most potent in vitro antiproliferative activity, with IC 50 <6.0 μM, compared to unmodified indomethacin having an IC 50 >100 μM.

N-(silylmethyl)amines, -amides, and -amino acids: biological activity and prospects in drug synthesis

“…They suppress cell growth of human pancreatic carcinoma MiaPaCa 2 at considerably lower concentrations than indometa cin (IC 50 < 6.0 μmol and IC 50 > 100 μmol, respect ively). 113,115,128 N Acetyl L cysteine 53 has a wide range of biological action on the organism and is used in medical practice as a mucolytic, antibiotical, and detoxication drug. In addi tion, compound 53 is a strong antioxidant.…”

Synthesis of lipophilic sila derivatives of N‐acetylcysteineamide, a cell permeating thiol

“…Aminomethyldimethylphenylsilane was synthesized as previously reported. [33] 1 H NMR spectra were obtained on a Varian Unity 500 spectrometer, 13 C {H} NMR spectra were obtained on a Varian Unity 500 spectrometer operating at 125 MHz, 29 Si {H} NMR spectra were obtained on a Varian Unity 500 spectrometer operating at 99 MHz. ESI mass spectra were determined on a VG AutoSpec M mass spectrometer.…”

“…[29] Sila-amidation of certain pharmacological agents has shown to increase potency and selectivity. [33,34] Silicon substitution onto the L-NAC molecule should lead to more lipophilic compounds of type 6, [34 -36] better able to penetrate across the gut wall and cell membranes. [36] This may result in improved pharmacological properties, [37,38] including bioavailability, metabolism and/or pharmacokinetics.…”

2-[2-(Trimethylsilyl)ethyl]isoindoline-1,3-dione

“…For literature related to drug design see: Bains & Tacke (2003); Bikzhanova et al (2007); Franz (2007); Franz et al (2007); ; Guzei,, Spencer, Zakai & Lynch (2010); ; Lee et al (1993Lee et al ( , 1996; Sen & Roach (1995); Showell & Mills (2003); Tacke & Zilch (1986); Tsuge et al (1985); Yoon et al (1991Yoon et al ( , 1992Yoon et al ( , 1997. For a description of the Cambridge Structural Database, see: Allen (2002).…”