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Discovery of Novel 4-Arylisochromenes as Anticancer Agents Inhibiting Tubulin Polymerization.

ABSTRACT: XJP-L (8), a derivative of the natural product (±)-7,8-dihydroxy-3-methylisochroman-4-one isolated from the peel of Musa sapien tum L., was found to exhibit weak inhibitory activity of tubulin polymerization (IC50 = 10.6 ?M) in our previous studies. Thus, a series of 4-arylisochromene derivatives were prepared by incorporating the trimethoxyphenyl moiety into 8, among which compound (±)-19b was identified as the most potent compound with IC50 values ranging from 10 to 25 nM against a panel of cancer cell lines. Further mechanism studies demonstrated that (±)-19b disrupted the intracellular microtubule network, caused G2/M phase arrest, induced cell apoptosis, and depolarized mitochondria of K562 cells. Moreover, (±)-19b exhibited potent in vitro antivascular and in vivo antitumor activities. Notably, the R-configured enantiomer of (±)-19b, which was prepared by chiral separation, was slightly more potent than (±)-19b and was much more potent than the S-configured enantiomer in both antiproliferative and antitubulin assays. Our findings suggest that (±)-19b deserves further research as a potential antitubulin agent for the treatment of cancers.

SUBMITTER: Li W

PROVIDER: S-EPMC6187416 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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Discovery of Novel 4-Arylisochromenes as Anticancer Agents Inhibiting Tubulin Polymerization.

Li Wenlong W Shuai Wen W Xu Feijie F Sun Honghao H Xu Shengtao S Yao Hong H Liu Jie J Yao Hequan H Zhu Zheying Z Xu Jinyi J

ACS medicinal chemistry letters 20180925 10

XJP-L (8), a derivative of the natural product (±)-7,8-dihydroxy-3-methylisochroman-4-one isolated from the peel of Musa sapien tum L., was found to exhibit weak inhibitory activity of tubulin polymerization (IC50 = 10.6 μM) in our previous studies. Thus, a series of 4-arylisochromene derivatives were prepared by incorporating the trimethoxyphenyl moiety into 8, among which compound (±)-19b was identified as the most potent compound with IC50 val ...[more]

PMID: 30344902

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Project description:The natural products colchicine and combretastatin A-4 (CA4) have been inspirational for the design and synthesis of structurally related analogues and spin-off compounds as inhibitors of tubulin polymerization. The discovery that a water-soluble phosphate prodrug salt of CA4 (referred to as CA4P) is capable of imparting profound and selective damage to tumor-associated blood vessels paved the way for the development of a new therapeutic approach for cancer treatment utilizing small-molecule inhibitors of tubulin polymerization that also act as vascular disrupting agents (VDAs). Combination of salient structural features associated with colchicine and CA4 led to the design and synthesis of a variety of fused aryl-cycloalkyl and aryl-heterocyclic compounds that function as inhibitors of tubulin polymerization. Prominent among these compounds is a benzosuberene analogue (referred to as KGP18), which demonstrates sub-nM cytotoxicity against human cancer cell lines and functions (when administered as a water-soluble prodrug salt) as a VDA in mouse models. Structure activity relationship considerations led to the evaluation of benzocyclooctyl [6,8 fused] and indene [6,5 fused] ring systems. Four benzocyclooctene and four indene analogues were prepared and evaluated biologically. Three of the benzocyclooctene analogues were active as inhibitors of tubulin polymerization (IC50 < 5 ?M), and benzocyclooctene phenol 23 was comparable to KGP18 in terms of potency. The analogous indene-based compound 31 also functioned as an inhibitor of tubulin polymerization (IC50 = 11 ?M) with reduced potency. The most potent inhibitor of tubulin polymerization from this group was benzocyclooctene analogue 23, and it was converted to its water-soluble prodrug salt 24 to assess its potential as a VDA. Preliminary in vivo studies, which utilized the MCF7-luc-GFP-mCherry breast tumor in a SCID mouse model, demonstrated that treatment with 24 (120 mg/kg) resulted in significant vascular shutdown, as evidenced by bioluminescence imaging at 4 h post administration, and that the effect continued at both 24 and 48 h. Contemporaneous studies with CA4P, a clinically relevant VDA, were carried out as a positive control.

Project description:To minimize treatment toxicities, recent anti-cancer research efforts have switched from broad-based chemotherapy to targeted therapy, and emerging data show that altered cellular metabolism in cancerous cells can be exploited as new venues for targeted intervention. In this study, we focused on, among the altered metabolic processes in cancerous cells, altered glycosylation due to its documented roles in cancer tumorigenesis, metastasis and drug resistance. We hypothesize that the enzymes required for the biosynthesis of UDP-hexoses, glycosyl donors for glycan synthesis, could serve as therapeutic targets for cancers. Through structure-based virtual screening and kinetic assay, we identified a drug-like chemical fragment, GAL-012, that inhibit a small family of UDP-hexose pyrophosphorylases-galactose pyro-phosphorylase (GALT), UDP-glucose pyrophosphorylase (UGP2) and UDP-N-acetylglucosamine pyrophosphorylase (AGX1/UAP1) with an IC50 of 30 µM. The computational docking studies supported the interaction of GAL-012 to the binding sites of GALT at Trp190 and Ser192, UGP2 at Gly116 and Lys127, and AGX1/UAP1 at Asn327 and Lys407, respectively. One of GAL-012 derivatives GAL-012-2 also demonstrated the inhibitory activity against GALT and UGP2. Moreover, we showed that GAL-012 suppressed the growth of PC3 cells in a dose-dependent manner with an EC50 of 75 µM with no effects on normal skin fibroblasts at 200 µM. Western blot analysis revealed reduced expression of pAKT (Ser473), pAKT (Thr308) by 77% and 72%, respectively in the treated cells. siRNA experiments against the respective genes encoding the pyrophosphorylases were also performed and the results further validated the proposed roles in cancer growth inhibition. Finally, synergistic relationships between GAL-012 and tunicamycin, as well as bortezomib (BTZ) in killing cultured cancer cells were observed, respectively. With its unique scaffold and relatively small size, GAL-012 serves as a promising early chemotype for optimization to become a safe, effective, multi-target anti-cancer drug candidate which could be used alone or in combination with known therapeutics.

Dataset Information

Discovery of Novel 4-Arylisochromenes as Anticancer Agents Inhibiting Tubulin Polymerization.

Publications

Discovery of Novel 4-Arylisochromenes as Anticancer Agents Inhibiting Tubulin Polymerization.

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