Synthesis and biological evaluation of anthraquinone derivatives as allosteric phosphoglycerate mutase 1 inhibitors for cancer treatment

Huang, Ke; Jiang, Lulu; Liang, Ronghui; Li, Huiti; Ruan, Xiaoxue; Shan, Changliang; Ye, Deyong; Zhou, Lu

doi:10.1016/j.ejmech.2019.01.085

Cited by 27 publications

(25 citation statements)

References 36 publications

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“…In this study, we investigate the function of PGAM1 in various types of cancer. PGAM1 is a glycolytic enzyme in nature that catalyzes the conversion of 2-phosphoglycerate and 3-phosphoglycerate [ 35 ]. PGAM1 overexpression in both 2PG and 3PG has additional biological functions and is affected in the anabolic condition.…”

Section: Resultsmentioning

confidence: 99%

In Silico Drug Screening Analysis against the Overexpression of PGAM1 Gene in Different Cancer Treatments

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El‐Esawi

El-Ballat

et al. 2021

BioMed Research International

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Phosphoglycerate mutase 1 (PGAM1) is considered as a novel target for multiple types of cancer drugs for the upregulation in tumor, cell prefoliation, and cell migration. During aerobic glycolysis, PGAM1 plays a critical role in cancer cell metabolism by catalyzing the conversion of 3-phosphoglycerate (3PG) to 2-phosphoglycerate (2PG). In this computational-based study, the molecular docking approach was used with the best binding active sites of PGAM1 to screen 5,000 Chinese medicinal phytochemical library. The docking results were three ligands with docking score, RMSD-refine, and residues. Docking scores were -16.57, -15.22, and -15.74. RMSD values were 0.87, 2.40, and 0.98, and binding site residues were Arg 191, Arg 191, Arg 116, Arg 90, Arg 10, and Tyr 92. The best compounds were subjected to ADMETsar, ProTox-2 server, and Molinspiration analysis to evaluate the toxicological and drug likeliness potential of such selected compounds. The UCSF-Chimera tool was used to visualize the results, which shows that the three medicinal compounds named N-Nitrosohexamethyleneimine, Subtrifloralactone-K, and Kanzonol-N in chain-A were successfully binding with the active pockets of PGAM1. The study might facilitate identifying the hit molecules that could be beneficial in the development of antidrugs against various types of cancer treatment. These hit phytochemicals could be beneficial for further investigation of a novel target for cancer.

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Section: Resultsmentioning

confidence: 99%

In Silico Drug Screening Analysis against the Overexpression of PGAM1 Gene in Different Cancer Treatments

Fareed

El‐Esawi

El-Ballat

et al. 2021

BioMed Research International

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“…N‐(1‐Hydroxy‐7‐nitro‐9‐oxo‐9H‐xanthen‐3‐yl)‐[1, 10‐biphenyl]‐4‐sulfonamide has been recently found as effective PGAM1 inhibitor with IC 50 value of 2.1 μM that is fivefold more potent than PGMI‐004A with effective antiproliferative activity against H1299 cells . A novel anthraquinone derivative was found to be most potent among known inhibitors of PGAM1 having EC 50 value of 97 nM with effective inhibitory potential against tumor growth in xenografted H1229 mouse model with no distant toxicity …”

Section: Pharmacological Inhibitors Of Pgam1mentioning

confidence: 99%

“…39 A novel anthraquinone derivative was found to be most potent among known inhibitors of PGAM1 having EC 50 value of 97 nM with effective inhibitory potential against tumor growth in xenografted H1229 mouse model with no distant toxicity. 49 EGCG is an important natural catechin that is obtained from green tea and discovered as potential PGAM1 inhibitor. (C) Xanthon EGCG attenuates glycolysis and oxidative PPP by reducing the intracellular level of 2-PG at 1 μM concentration.…”

Section: Pharmacological Inhibitors Of Pgam1mentioning

confidence: 99%

Phosphoglycerate mutase 1 in cancer: A promising target for diagnosis and therapy

et al. 2019

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Altered enzymatic machineries are a substantial biochemical characteristic of tumor cell metabolism that switch metabolic profile from oxidative phosphorylation to amplified glycolysis as well as increased lactate production under hypoxia conditions. Reprogrammed metabolic profile is an emerging hallmark of cancer. Overexpression of several glycolytic enzymes and glucose transporters has been reported in 24 different types of cancers that represent approximately 70% of all the cancer cases around the globe. Thus, targeting glycolytic enzymes could serve as tempting avenue for drug design against cancer. Phosphoglycerate mutase 1 (PGAM1) is an important glycolytic enzyme that catalyzes the conversion of 3‐phosphoglycerate to 2‐phosphoglycerate. Recent investigations have revealed the overexpression of PGAM1 in several human cancers that is linked with tumor growth, survival, and invasion. The aim of this review is to update scientific research network with cancer‐specific role of PGAM1 to elucidate its capability as bonafide therapeutic target for cancer therapy. Moreover, we have also summarized the reported genetic and pharmacological inhibitors of PGAM1. This study suggests that further investigations on PGAM1 should focus on the exploration of molecular mechanisms of PGAM1 overexpression in development of cancer, assessment of biosafety profiles of known inhibitors of PGAM1, and utilization of PGAM1 inhibitors in combinatorial therapies. These future studies will surely support the unbiased strategies for the development of novel PGAM1 inhibitors for cancer therapies.

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“…PGAM1 is over expressed in numerous kinds of aggressive human cancers mainly breast, prostate, lung, colorectal, hepatocellular carcinoma and pancreatic ductal adenocarcinoma (Sharif et al, 2019). Previous studies have also demonstrated that PGAM1-mediated glycolysis plays critical role in tumor development, survival, and migration of cancer cells (Huang et al, 2019), thus, PGAM1 inhibition has potential to kill cancer cells selectively.…”

Section: Introductionmentioning

confidence: 99%

Untitled

2021

Pak. J. Pharm. Sci

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Targeting cancer-specific metabolic and mitochondrial remodeling has emerged as a novel and selective strategy for cancer therapy during recent years. Phosphoglycerate Mutase 1 (PGAM1) is an important glycolytic enzyme that catalyzes the conversion of 3-phosphoglycerate to 2-phosphoglycerate and plays a critical role in cancer progression by coordinating glycolysis and biosynthesis. PGAM1 has been reported to be over expressed in a variety of cancer types and its inhibition results in decreased tumor growth and metastasis. Recently, there has been a growing interest in identification and characterization of novel PGAM1 inhibitors for the treatment of cancer. In the current study, in silico tools were used to find out natural inhibitors of PGAM1. For docking studies, a database of 5006 phytochemicals were docked against PGAM1, using MOE software in order to identify the compounds which show better binding affinities than PGMI-004A. Out of 5006 compounds screened, eight compounds (1,3-cyclopentanedione, glyflavanone B, 6demethoxytangeretin, gnaphaliin, lantalucratin A and -(-) morelensin, abyssinin II and monotesone-A) showed significant binding affinity with PGAMI active site. Further, the eight selected compounds were evaluated for different pharmacokinetics parameters using admetSAR, the obtained results demonstrated that none of these hit compounds violated Lipinski's drug rule of 5 and all the hit compounds possess favorable ADMET properties. This study has unveiled the potential of phytochemicals that could serve as probable lead candidates for the development of PGAM1 inhibitors as anti-cancer agents.

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Synthesis and biological evaluation of anthraquinone derivatives as allosteric phosphoglycerate mutase 1 inhibitors for cancer treatment

Cited by 27 publications

References 36 publications

In Silico Drug Screening Analysis against the Overexpression of PGAM1 Gene in Different Cancer Treatments

In Silico Drug Screening Analysis against the Overexpression of PGAM1 Gene in Different Cancer Treatments

Phosphoglycerate mutase 1 in cancer: A promising target for diagnosis and therapy

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