A review on pharmacophoric designs of antiproliferative agents

Abstract

Past few decades have witnessed the dawn of new diseases in which cancer is a major problem and the race ensued to eradicate cancer by charting out various effective therapeutic regimens.

Dual Abrogation of Mnk and Mtor: A Novel Therapeutic Approach for the Treatment of Aggressive Cancers

“…This has prompted the development of HDAC inhibitor containing hybrid agents, for example, a recently synthesized dual HDAC/VEGFR2 inhibitor [114]. Another promising agent, CUDC-101, developed by Curis, was found to simultaneously inhibit HDAC class I/II, EGFR and HER2 and exhibited antiproliferative effects in vitro and growth inhibition in various cancer xenograft models [121]. It is currently being investigated in combination with radiation and other agents such as cisplatin in HSNCC [122].…”

Imine/amide–imidazole conjugates derived from 5-amino-4-cyano- N 1-substituted benzyl imidazole: Microwave-assisted synthesis and anticancer activity via selective topoisomerase-II-α inhibition

“…2 In continuation of our previous efforts towards anticancer drug discovery [4][5][6][7][8][9] and development, 10 we thought of designing hybrid pharmacophores derived from imine-imidazoles and imineamides ( Fig. 1) in which one of the aromatic rings of stilbenes 11,12 / imines (1) or benzamides (2) was substituted with imidazole scaffold, that is, 5-amino-4-cynao-N1-substituted benzyl imidazole (3). This is anticipated to solve the issue of limited bioavailability due to glucuronidation and sulfation as observed with most of stilbenes and offer an alternative strategy other than acetylation 13 and methylation.…”

“…Persistent failure in anticancer drug development prompted the researchers to use the strategies of combining pharmacophores as targeted therapeutic agents. 2 These drugs have the potential to overcome the fast development of resistance, enhance patient compliance, and reduce both the cost and the risk of drug-drug interactions. 3 The scope of molecular hybridization can be clearly exemplified through the US-FDA approved estramustine and successful ongoing of other hybrid molecules that are currently in different phases of clinical trials such as CUDC-101, CBLC-137, PLX3397, E-3810, and CUDC-907.…”

“…3 The scope of molecular hybridization can be clearly exemplified through the US-FDA approved estramustine and successful ongoing of other hybrid molecules that are currently in different phases of clinical trials such as CUDC-101, CBLC-137, PLX3397, E-3810, and CUDC-907. 2 In continuation of our previous efforts towards anticancer drug discovery [4][5][6][7][8][9] and development, 10 we thought of designing hybrid pharmacophores derived from imine-imidazoles and imineamides ( Fig. 1) in which one of the aromatic rings of stilbenes 11,12 / imines (1) or benzamides (2) was substituted with imidazole scaffold, that is, 5-amino-4-cynao-N1-substituted benzyl imidazole (3).…”

Pyrimidine containing epidermal growth factor receptor kinase inhibitors: Synthesis and biological evaluation

“…[12,13] However, early Phase I clinical trials of third-generation EGFR inhibitors are found to be promising and effective, but they are likely to produce off-target side-effects and toxicities after their prolonged use. [14,15] Thus, based on our previous experiences in anticancer drug discovery, [16][17][18][19][20][21][22][23][24] we have designed the target compounds (Figure 2) considering the common pharmacophoric features of erlotinib (reversible) and WZ4002 (irreversible) [25] with the assumptions that compounds should: (a) possess pyrimidine ring with 2-alkoxy/ hydroxyl aniline moiety for hydrogen bond interaction with MET793, (b) be able to selectively target hypoxic tumours by possessing nitro substituent on either or both the aromatic rings with/without solubility enhancer due to their bioreduction to yield electrophilic substances which are capable of damaging protein and nucleic acids [24,26] and have radiosensitizing ability, [27] (c) be reversible and non-covalent in nature as irreversible inhibitors not only make covalent interactions with CYS797 of target but also undergo conjugate addition with other nucleophiles in the body due to their Michael acceptor property, thereby leading to off-target side-effects and, (d) be easy to synthesize and cost-effective.…”