The Design and Synthesis of N-Xanthone Benzenesulfonamides as Novel Phosphoglycerate Mutase 1 (PGAM1) Inhibitors

Abstract

Upregulation of phosphoglycerate mutase 1 (PGAM1) has been identified as one common phenomenon in a variety of cancers. Inhibition of PGAM1 provides a new promising therapeutic strategy for cancer treatment. Herein, based on our previous work, a series of new N-xanthone benzenesulfonamides were discovered as novel PGAM1 inhibitors. The representative molecule 15h, with an IC50 of 2.1 μM, showed an enhanced PGAM1 inhibitory activity and higher enzyme inhibitory specificity compared to PGMI-004A, as well as a slightly improved antiproliferative activity.

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

“…Silencing of PGAM1 expression diminishes the prostate cancer (PCa) cell proliferation, invasion potential, and induces apoptosis through downregulation of MMP‐2 and MMP‐9 proteins . Deficiency of PGAM1 by PGAM1‐004A, which is the small molecule inhibitor, escalates the intracellular 3‐PG level and reduces 2‐PG level ultimately suppressing the Pancreatic Ductal Adenocarcinoma (PDAC) …”

“…Later on the reversal strategy for sulfonamide was used to make a series of xanthone derivatives that switched the anthraquinone core of PGMI‐004A with xanthone core, which showed 26 times inhibitory efficacy than PGMI‐004A (Figure ). 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 …”

“…35 Deficiency of PGAM1 by PGAM1-004A, which is the small molecule inhibitor, escalates the intracellular 3-PG level and reduces 2-PG level ultimately suppressing the Pancreatic Ductal Adenocarcinoma (PDAC). 39…”

“…Three small molecules MJE3, PGMI-004A, and epigallocatechin gallate (EGCG) have been revealed as PGAM1 inhibitors in last few years. 39 MJE3 is a cell-permeable, smallmolecule inhibitor of PGAM1 that is found to be efficient in inhibiting the proliferation of human breast carcinoma cells (IC 50 = 33 μM). MJE3 has the ability to inhibit PGAM1 via covalent modification of PGAM1's Lysine 100 (K100) by its spiro-epoxide pharmacophore.…”

“…N-(1-Hydroxy-7-nitro-9-oxo-9Hxanthen-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. 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.…”