D-64131

D-64131 is a tubulin polymerization inhibitor with an IC50 value of 0.53 μM. [1]

The polymerization of bovine brain tubulin as well as binding of [3H] colchicine to biotinylated αβ-tubulin was dose-dependently inhibited by D-64131. Many cancer cells display abnormal microtubule structures, such as fragmented mitotic spindles or multiple spindle poles after treatment with D-64131. Nuclear blebbing and abnormal nuclear structures typical for apoptotic cells are detectable in many cells treated with D-64131. In nude mice, D-64131 proved to be well tolerated and highly active against the human amelanoic melanoma MEXF 989 tumor xenograft. D-64131 treatment resulted in significant tumor growth inhibition during treatment. [1]

Reference:
1. Beckers T, Reissmann T, Schmidt M et al.  2-aroylindoles, a novel class of potent, orally active small molecule tubulin inhibitors. Cancer Res. 2002 Jun 1;62(11):3113-9.

Dual visible-light photoredox and palladium(ii) catalysis for dehydrogenative C2-acylation of indoles at room temperature.[Pubmed:28682380]

Org Biomol Chem. 2017 Jul 19;15(28):5899-5903.

A highly regioselective direct C2-acylation of N-pyrimidine protected indoles with aldehydes is reported at room temperature through the merger of visible light photoredox and palladium(ii) catalysis. Late-stage acylation of tryptophan, selective mono-acylation of carbazole and the syntheses of tubulin inhibitors D-64131 and D-68144 are also demonstrated.

Indolobenzazepin-7-ones and 6-, 8-, and 9-membered ring derivatives as tubulin polymerization inhibitors: synthesis and structure--activity relationship studies.[Pubmed:19743863]

J Med Chem. 2009 Oct 8;52(19):5916-25.

Several small weight indole derivatives (D-64131, D-24851, BPR0L075, BLF 61-3, and ATI derivatives) are potent tubulin polymerization inhibitors and show nanomolar antiproliferative activity. Among them, indolobenzazepin-7-ones were recently disclosed as potent antimitotic agents. In an effort to improve this structure, we prepared new derivatives in order to evaluate their antiproliferative activity. 5,6,7,9-Tetrahydro-8H-indolo[2,3-e][3]benzazocin-8-one (1m) was found to be the most potent derivative inhibiting the cell growth of several cancer cell lines in the lower nanomolar range.

2-aroylindoles, a novel class of potent, orally active small molecule tubulin inhibitors.[Pubmed:12036922]

Cancer Res. 2002 Jun 1;62(11):3113-9.

2-Aroylindoles with 5-methoxy-1H-2-indolyl-phenylmethanone (D-64131) as the lead structure were discovered as a new class of synthetic, small molecule tubulin inhibitors. By competitively binding with [(3)H]colchicine to alphabeta-tubulin and inhibiting microtubule formation, cycling cells were arrested in the G(2)-M phase of the cell division cycle. The proliferation of tumor cells from 12 of 14 different organs and tissues was inhibited with mean IC(50)s of 62 nM and 24 nM by D-64131 and D-68144, respectively, comparable with the potency of paclitaxel with mean IC(50) of 10 nM. By measuring the cytotoxicity in a human colon carcinoma cell model with ectopic ecdysone-inducible expression of the cyclin-dependent kinase inhibitor p21(WAF1), specificity toward cycling cells was demonstrated. In contrast to microtubule inhibitors from natural sources, 2-aroylindoles did not alter the polymerization-dependent GTPase activity of beta-tubulin and are not substrates of the multidrug resistance/multidrug resistance protein efflux pump. No cross-resistance toward cell lines with multidrug resistance/multidrug resistance protein independent resistance phenotypes became evident. In animal studies, no signs of systemic toxicity were observed after p.o. dosages of up to 400 mg/kg of D-64131. In xenograft experiments with the human amelanoic melanoma MEXF 989, D-64131 was highly active with treatment resulting in a growth delay of 23.4 days at 400 mg/kg. Therefore, D-64131 and analogues have the potential to be developed for cancer therapy, replacing or supplementing standard therapy regimens with tubulin-targeting drugs from natural sources.

Synthetic 2-aroylindole derivatives as a new class of potent tubulin-inhibitory, antimitotic agents.[Pubmed:11741473]

J Med Chem. 2001 Dec 20;44(26):4535-53.

A new class of simple synthetic antimitotic compounds based on 2-aroylindoles was discovered. (5-Methoxy-1H-2-indolyl)-phenylmethanone (1) as well as analogous 3-fluorophenyl- (36) and 3-methoxyphenyl (3) derivatives displayed high cytotoxicity of IC(50) = 20 to 75 nM against the human HeLa/KB cervical, SK-OV-3 ovarian, and U373 astrocytoma carcinoma cell lines. The inhibition of proliferation correlated with the arrest in the G2/M phase of the cell cycle. In in vitro assays with tubulin isolated from bovine brain, in general antiproliferative activity correlated with inhibition of tubulin polymerization. Thus, the antimitotic activity of 2-aroylindoles is explained by interference with the mitotic spindle apparatus and destabilization of microtubules. In contrast to colchicine, vincristine, nocodazole, or taxol, 1 did not significantly affect the GTPase activity of beta-tubulin. Interestingly, selected compounds inhibited angiogenesis in the chorioallantoic membrane (CAM) assay. In xenograft experiments, 1 was highly active after oral administration at 200 mg/kg against the human amelanocytic melanoma MEXF 989 in athymic nude mice. We conclude, that 2-aroylindoles constitute an interesting new class of antitubulin agents with the potential to be clinically developed for cancer treatment.