Investigating Structural Requirements for the Antiproliferative Activity of Biphenyl Nicotinamides

Abstract

A number of trimethoxybenzoic acid anilides, previously studied as permeability glycoprotein (P-gp) modulators, were screened with the aim of identifying new anticancer agents. One of these compounds, which showed antiproliferative activity against resistant MCF-7 cell line, was selected as the hit structure. Replacement of the trimethoxybenzoyl moiety with a nicotinoyl group, in order to overcome solubility issues, led to a new series of N-biphenyl nicotinoyl anilides, among which a nitro derivative, N-(3',5'-difluoro-3-nitro-[1,1'-biphenyl]-4-yl)nicotinamide (3), displayed antiproliferative activity against MCF-7 and MDA-MB-231 cells in the nanomolar range. The search for a bioisostere of the nitro group led to nitrile analogue N-(3-cyano-4'-fluoro-[1,1'-biphenyl]-4-yl)nicotinamide (36), which shows a strong increase in activity against MCF-7 and MDA-MB-231 cells. Compound 36 induced a dose-dependent accumulation of G - and M-phase MCF-7 cell populations, and a decrease in S-phase cells. Relative to vinblastine, a well-known potent antimitotic agent, compound 36 also induced G -phase arrest at low doses (20-40 nm), but did not inhibit in vitro tubulin polymerization.

Hydroxy-Propil-β-Cyclodextrin Inclusion Complexes of two Biphenylnicotinamide Derivatives: Formulation and Anti-Proliferative Activity Evaluation in Pancreatic Cancer Cell Models

“…The synthesis of PTA34 (MW = 337.30) and PTA73 (MW = 319.30) was performed according to the already reported literature procedure [ 6 , 7 ]. HP-β-CD (hydroxypropil-β-cyclodextrin, MW = 1396 Dalton, substitution degree 0.65) was purchased from Farmalabor (Canosa, Italy).…”

“…In this scenario, in order to identify new therapeutic strategies for PDAC, we planned to investigate, in a PDAC cells panel, the pharmacological efficacy of two newly synthesized N-biphenylnicotinamides, namely PTA34 and PTA73 [ 6 , 7 ], formulated as hydroxy-propil-β-cyclodextrin (HP-β-CD) inclusion complexes ( Figure 1 ).…”

Synthesis and Cytotoxic Activity of Chiral Sulfonamides Based on the 2-Azabicycloalkane Skeleton

“…In addition to functional groups, certain characteristic structural motifs are also associated with impressive biological activity. For example, the biphenyl moiety is present in numerous derivatives that have been tested in antiproliferative studies [6][7][8]. The trifluoromethyl group is also regarded as a valuable pharmacophore [9], which is found in marketed drugs (e.g., nonsteroidal antiandrogen flutamide) and newly developed derivatives [10].…”

Novel Antiproliferative Biphenyl Nicotinamide: NMR Metabolomic Study of its Effect on the MCF-7 Cell in Comparison with Cisplatin and Vinblastine

“…To this regard, besides the combination therapies, the development of systematic methods for metabolomics is a promising strategy and tool for improving diagnosis and treatment [ 4 , 5 ]. In recent years, some of us investigated the potential anti-proliferative activity of an in-house synthesized library of diverse N -biaryl amides, including trimethoxybenzamides (e.g., 1 , Figure 1 ) [ 6 , 7 ] and nicotinamides (e.g., 2 and 3 , Figure 1 ) [ 8 , 9 ], with some of them showing very high antiproliferative activity against human breast cancer cell lines MCF-7 and MDA-MB231 [ 8 ]. The 2,4,5-trimethoxybenzanilide derivative 1 , which proved to be a potent P-glycoprotein (P-gp) inhibitor [ 6 ], was taken as the hit compound for an optimization study aimed at disclosing new chemical entities active toward P-gp-mediated multidrug resistant tumor cells.…”

“…A number of replacements were designed for improving pharmacokinetics-related properties (e.g., water solubility) while retaining good antiproliferative effect against breast cancer, which is a major cause of women’s morbidity and mortality [ 2 ]. Among the synthesized compounds, the nicotinamide derivative 2 proved to inhibit the growth of MCF-7 and MDA-MB231 cell lines with IC50′s in the nanomolar range (250 and 229 nM, respectively) and tubulin polymerization at 3 μM concentration [ 6 ], whereas the bioisosteric replacement of NO 2 with the nitrile CN group led to the nicotinamide derivative 3 (lab code DT-8) showing IC 50 values equal to 47 and 37 nM on MCF-7 and MDA-MB231 cells, respectively [ 8 ].…”