Targeting human MutT homolog 1 (MTH1) for cancer eradication: current progress and perspectives

Since accelerated metabolism produces much higher levels of reactive oxygen species (ROS) in cancer cells compared to ROS levels found in normal cells, human MutT homolog 1 (MTH1), which sanitizes oxidized nucleotide pools, was recently demonstrated to be crucial for the survival of cancer cells, but not required for the proliferation of normal cells. Therefore, dozens of MTH1 inhibitors have been developed with the aim of suppressing cancer growth by accumulating oxidative damage in cancer cells. While several inhibitors were indeed confirmed to be effective, some inhibitors failed to kill cancer cells, complicating MTH1 as a viable target for cancer eradication. In this review, we summarize the current status of developing MTH1 inhibitors as drug candidates, classify the MTH1 inhibitors based on their structures, and offer our perspectives toward the therapeutic potential against cancer through the targeting of MTH1.

(1H-Pyrrolo [2,3-b]pyridine)7-Azaindole Derivatives and Their Antiurease, Phosphodiesterase and ẞ-glucuronidase Activity.

A variety of 7-azaindole analogs 1-14 with variable substituents on phenyl ring of phenacyl moiety were synthesized and evaluate for their urease, phosphodiesterase and -glucuronidase Inhibitory potential. Compound 9 (IC50 = 2.19±0.37μM) showed potent urease inhibitory potential than standard thiourea (IC50 = 21.00±0.01μM). However, while compounds 10 (IC50 = 255.11±6.62μM) and 8 (IC50 = 133.3±0.46μM), exhibited moderate urease potential. Moreover, compound 2 (IC50 = 20.83± 0.234μM) showed potent phosphodiesterase inhibitory potential than standard EDTA (IC50 = 274.00+0.007μM). Compound 8 (IC50 192.6±3.53μM) was found to be moderate ẞ-glucuronidase inhibitor, as compare to standard 1,4, lactone D saccharic acid (IC50 = 48.41±1.24μM). Nevertheless, compounds 13 (36.81% inhibition) and 14 (47.11% inhibition) showed less than 50% ẞ-glucuronidase inhibition, therefore they were not further evaluated for their IC50 values. The size of the substituent, electron donating or withdrawing affect of substituents as well as the position of substituent on phenyl affects the activity.

(1H-Pyrrolo [2,3-B] Pyridine) 7-Azaindole as Cholinesterase/ Glycation Inhibitors.

As a part of our program to discover novel analoges of (1H-pyrrolo [2,3-b] pyridine) 7- azaindole having useful biological activities, a variety of 7-azaindole analogs 1-9 with variable substituents on phenyl ring of phenacyl moiety were synthesized and evaluated for their AChE, BChE and antiglycation Inhibitory potential. Compounds 2-5 were found to be AChE inhibitors with IC50 1.34 μM, 11.60 μM, 0.96 μM and 0.97 μM respectively, while compounds 2-5 were also found to be BChE inhibitors with IC50 1.25 μM, 3.93 μM, IC50 9.18μM and 10.20μM respectively. Compounds 2 (IC50 = 1.25±0.019uM) and 3 (IC50 = 3.93±0.36uM), showed potent BChE inhibitory potential than standard Galantamine (IC50 = 8.51±0.02uM). Besides this, compounds 2-9 were evaluated for glycation inhibition activity. Compound 5 (IC50 values 120.6+0.2uM) showed potent antiglycation potential than standard rutin (IC50=294.50+1.5uM). The size of the substituent, electron donating or withdrawing effect of substituents as well as the position of substituent on phenyl effects the activity.