Synthesis and SAR Analysis of Novel 4-Hydroxytamoxifen Analogues Based on Their Cytotoxic Activity and Electron-Donor Character

Abstract

Utilizing McMurry reactions of 4,4′-dihydroxybenzophenone with appropriate carbonyl compounds, a series of 4-Hydroxytamoxifen analogues were synthesized. Their cytotoxic activity was evaluated in vitro on four human malignant cell lines (MCF-7, MDA-MB 231, A2058, HT-29). It was found that some of these novel Tamoxifen analogues show marked cytotoxicity in a dose-dependent manner. The relative ROS-generating capability of the synthetized analogues was evaluated by cyclic voltammetry (CV) and DFT modeling studies. The results of cell-viability assays, CV measurements and DFT calculations suggest that the cytotoxicity of the majority of the novel compounds is mainly elicited by their interactions with cellular targets including estrogen receptors rather than triggered by redox processes. However, three novel compounds could be involved in ROS-production and subsequent formation of quinone-methide preventing proliferation and disrupting the redox balance of the treated cells. Among the cell lines studied, HT-29 proved to be the most susceptible to the treatment with compounds having ROS-generating potency.

Quantum Chemical-Based Investigations and Lipophilicity Evaluations on Some Structurally Related Quinazoline Derivatives

“…Stabilization energy values were calculated according to the formula specified in equation (10). The terms in the formula are expressed as follows: E (2) : Stabilization energy, qi: Donor orbital occupancy, Fij: Off diagonal Fock matrix, ɛi and ɛj: diagonal element, donor and acceptor orbital energies.…”

“…As shown in Figure 1, quinazoline (1) is a pyrimidine compound and can be classified as quinazolin-2(1H)-one (2) and quinazolin-4(3H)-one (3) [7]. To date, a wide variety of pharmacological activities of quinazoline derivatives have been reported (Figure 1) [8][9][10].…”

The significance of quinazoline derivatives as potential multi-target anti-cancer agents: review article

“…The heterocycles are extensively studied bioactive compounds and are regarded as crucial synthetic targets for developing new therapeutics [16][17][18]. The biological uses of quinazoline, one of the heterocycles, have been the subject of much investigation [19][20][21].…”