Stability of the Phosphotriester PDE6D Inhibitors

Abstract

The kinetics for the cleavage of the phosphotriester PDE6D inhibitors 1 (Deltaflexin‐2) and 3 (Deltaflexin‐1) and their derivatives 2, 4 and 5 is presented under various conditions in aqueous solutions. The conversion of the phosphotriesters (1–5) into the phosphodiesters 1**–5** was detected to take place as a major degradation process. In the absence of enzyme, the 4‐acetylthio‐2,2‐dimethyl‐3‐oxobutyl protected compounds (1, 4 and 5) are one order of magnitude more stable than the 4‐acetylthio‐2‐ethoxycarbonyl‐3‐oxo‐2‐methylbutyl protected ones (2 and 3). In cell culture (DMEM) containing fetal bovine serum and l‐glutamine, an intermediary formation of S−S‐dimer competed with the removal of the protecting group after deacetylation of the starting material. In addition, the susceptibility of the compounds to amine nucleophiles as well as their stability under acidic and basic condition were determined in non‐aqueous solutions.

DFT and molecular simulation validation of the binding activity of PDEδ inhibitors for repression of oncogenic k-Ras

“…They possessed potent anti-proliferative activity on breast and colorectal tumors, as well as the ability to suppress lung and breast cancer stemness traits [15]. These compounds were able to repress around a 1000 times difference in effectiveness between in vitro and in cellulo due to presence of biodegradable cell penetration group [26,27]. It was proposed that key interactions between the hydrophobic cavity of PDEδ and the farnesyl group of Ras family alongside interactions with Arg61 and Tyr149 can put the inserted molecule into the receptor's binding site of PDEδ's in the correct orientation [28,29].…”

5'‐O‐(2‐Isopropoxyprop‐2‐yl)‐protected Phosphoramidite Building Blocks in the Liquid Phase Oligonucleotide Synthesis

“…To make ON manufacturing more sustainable and process compatible, [2] robust synthesis strategies, which work entirely in solution (i. e., Liquid Phase Oligonucleotide Synthesis, LPOS) have attracted growing interest [3–5] . The advanced methods are based on soluble supports, which facilitate isolation of the growing ONs from the reaction media either by membrane filtration or precipitation [6–16] . In addition, a marked achievement has recently been done in a convergent approach, which ligates tetra‐ and pentameric fragments to gain full‐length ON products [17] …”

“…[3][4][5] The advanced methods are based on soluble supports, which facilitate isolation of the growing ONs from the reaction media either by membrane filtration or precipitation. [6][7][8][9][10][11][12][13][14][15][16] In addition, a marked achievement has recently been done in a convergent approach, which ligates tetra-and pentameric fragments to gain full-length ON products. [17] LPOS may need re-evaluation of the ON protecting group scheme.…”

“…-NMR (400 MHz, CDCl 3 ) δ 4.04 (septet, J = 6.15 Hz, 2H, isopropoxy OCH(Me) 2 ), 1.35 (s, 6H, acetal OC(CH 3 ) 2 O)), 1.15 (d, J = 6.15 Hz, 12H, isopropoxy OCH(CH 3 ) 2 );13 C-NMR (125 MHz, CDCl 3 ) δ 100.18 (OC-(Me) 2 O), 62.37 (OCH(Me) 2 ), 27.02 (OC(CH 3 ) 2 O), 24.44 (OCH(CH 3 ) 2 ). isopropoxyprop-2-yl)-3'-O-tertbutyldimethylsilyl-2'-deoxynucleosides 3 a-3 d: Typically, 18 mmol of the appropriate protected nucleoside (2 a-2 d) was dissolved in anhydrous dichloromethane…”