Anticancer properties of novel pyrazole‐containing biguanide derivatives with activating the adenosine monophosphate‐activated protein kinase signaling pathway

Abstract

Biguanides, including metformin and phenformin, have emerged as promising anticancer agents. However, the high dose needed for their efficient anticancer properties restricts their clinical application. In an attempt to obtain higher active compounds than these parent compounds, pyrazole-containing biguanide derivatives were synthesized and screened for in vitro cytotoxicity against human cancer cell lines. Clonogenic assays and scratch wound healing assays demonstrated that these new derivatives profoundly inhibit cell proliferation and migration. Compounds 10b and 10d exhibited strong potency with low IC 50 values in the range of 6.9-28.3 μM, far superior to phenformin and metformin. Moreover, 20 μM 10b and 10d resulted in 72.3-88.2% (p < 0.001) inhibition of colony formation and 29.3-60.7% (p < 0.05) inhibition of cell migration. Mechanistically, 10b and 10d activated adenosine monophosphate-activated protein kinase, leading to inactivation of the mammalian target of rapamycin (mTOR) signaling pathway with the regulation of 4EBP1 and p70S6K. These results suggest the value of these novel biguanide derivatives as candidates with therapeutic potential for the treatment of bladder and ovarian cancer. K E Y W O R D S AMPK, anticancer, biguanide, pyrazole-containing heterocyclic compounds

Redox Homeostasis and Metabolism in Cancer: A Complex Mechanism and Potential Targeted Therapeutics

“…Bladder and ovarian cancer cell lines exposed to increasing concentrations of metformin and phenformin isomers of showed dramatic growth inhibition with more potent inhibitory effects of phenformin on proliferation and colony formation assays as well as a synergistic effect with the EGFR inhibitor gefitinib [182]. The proposed mechanism of inhibition of tumorigenic growth involved AMPK activation leading to the inhibition of the mTOR pathway with further downregulation of its downstream effectors, 4EP1 and p70S6K [183]. Lea et al [181] demonstrated that phenformin inhibited the growth and glucose uptake of bladder and colon cancer cell lines through the inhibition of AKT and ERK1/2.…”

Synthesis, Anti-Proliferative Evaluation and Mechanism of 4-Trifluoro Methoxy Proguanil Derivatives with Various Carbon Chain Length

“…Since there is no significant difference in the anti-proliferative activity between 5C to 8C while compounds with longer carbon chain than 8C have poorer activity than that of proguanil, we selected the compound 8C as a representative compound to investigate the pharmacological mechanism. Previously, our research group has proved that biguanide derivatives can exert anti-tumor effects through AMPK/mTOR pathway [ 19 ]. Adenosine 5’-monophosphate (AMP)-activated protein kinase (AMPK) is a key molecule in the regulation of bioenergy metabolism [ 20 ], and it is the core of the study of diabetes and other metabolic-related diseases [ 21 , 22 ].…”

Synthetic accesses to biguanide compounds

“…pared various N 1 -mono-and N 1 ,N 1 -disubstituted aryl-and alkylbiguanides with yields up to 97%, despite great variability in the case of alkylbiguanides (Scheme 8A) [24]. Recently, Zhou et al reported similar conditions applied for the synthesis of anticancer biguanides [25]. The conditions chosen for the synthesis of a small library of pyrazole-containing biguanide derivatives were 2 equivalents of dicyandiamide and 2.2 equivalents of trimethylsilyl chloride in dry acetonitrile under MW irradiation (200-400 W) for 15 min at 140 °C.…”