A series of pyrrole-indolin-2-ones were synthesized, and their inhibition profile for Aurora kinases was studied. The potent compound 33 with phenylsulfonamido at the C-5 position and a carboxyethyl group at the C-3' position selectively inhibited Aurora A over Aurora B with IC50 values of 12 and 156 nM, respectively. Replacement of the carboxyl group with an amino group led to compound 47, which retained the activity for Aurora B and lost activity for Aurora A (IC50=2.19 microM). Computation modeling was used to address the different inhibition profiles of 33 and 47. Compounds 47 and 36 (the ethyl ester analogue of 33) inhibited the proliferation of HCT-116 and HT-29 cells and suppressed levels of the phosphorylated substrates of Aurora A and Aurora B in the Western blots.

No abstract

Through the syntheses of its C-1 desvinyl, C-7 methylene, C-7 exocyclic ethylidene, and various C-3 phenylmethyl analogues, the structure−activity relationship of antimitotic ottelione A (4) against tubulin and various cancer cells was established. The results indicated that compound 4 was a colchicine-competitive inhibitor and that the C-1 vinyl group is unnecessary for its potency, whereas the C-7 exocyclic double bond is essential, possibly because of its irreversible interaction with tubulin. Further optimization of the substituents on the phenylmethyl group at the C-3 position generated compound 10g with a 3′-fluoro-4′-methoxyphenylmethyl substituent, which was 6−38-fold more active against MCF-7, NCI-H460, and COLO205 cancer cells relative to 4. Results from in vitro tubulin polymerization assay confirmed the potency of compounds 4, 10g, and 11a. KEYWORDS: ottelione A, antimitotic, microtubule, tubulin, anticancer A fter the success of antimitotic taxanes and vinca alkaloids as anticancer drugs, 1,2 antimitotic agents that target the colchicine-binding site to inhibit tubulin polymerization have attracted much attention. Many structurally diverse compounds binding to the colchicine-binding site have been discovered from natural or synthetic sources. 3,4 Despite no compound of this class having been approved for clinical use, the prototype colchicine (1, Figure 1) has been used to treat gout for many years.5 Combretastatin A-4 (2) 6−9 and ABT-751 (3) 10,11 in Figure 1 are representative examples of colchicine-competitive inhibitors currently in clinical trials to treat various cancers.Ottelione A (4, Figure 1), isolated from the fresh water plant Ottelia alismoides collected in the Nile Delta, 12 is among the most potent natural products that possess in vitro antiproliferative activity. Its IC 50 values lie in the pM−nM range against a panel of 60 human cancer cell lines through acting as a colchicine-competitive inhibitor. 12,13 Because of its promising antitumor activity and intriguing core structure with four stereogenic centers, several synthetic groups have investigated the total synthesis of 4, 14−21 but no analogue has been reported and assayed for anticancer activity, perhaps because of the many steps in its preparation.We already achieved an enantioselective total synthesis of 4 using our α-carbonyl radical cyclization method. 21 The bicyclo[4.3.0]nonane core structure was constructed via radical cyclization. The C-3 3′-hydroxy-4′-methoxyphenylmethyl group, C-1 vinyl group, and C-7 exocyclic double bond were then sequentially introduced. We thus envisaged that our scheme could be adaptable for the preparation of various analogues of 4, which would be useful to establish its structure−activity relationship.As shown in Scheme 1, we first prepared compounds 10a−g and 11a−c according to our scheme for the total synthesis of 4. For economy, these compounds were all synthesized in their racemic forms. Compound 5, prepared via α-carbonyl radical cyclization, 21 served as the starting material. H...

In this paper, we present a copper­(I)-catalyzed nitrile-addition/N-arylation ring-closure cascade for the synthesis of 5,11-dihydro-6H-indolo­[3,2-c]­quinolin-6-ones from 2-(2-bromophenyl)-N-(2-cyanophenyl)­acetamides. Using CuBr and t-BuONa in dimethylformamide (DMF) as the optimal reaction conditions, the cascade reaction gave the target products, in high yields, with a good substrate scope. Application of the cascade reaction was demonstrated on the concise total syntheses of alkaloid isocryptolepine. Further optimization of the products from the cascade reaction led to 3-chloro-5,12-bis­[2-(dimethylamino)­ethyl]-5,12-dihydro-6H-[1,3]­dioxolo­[4′,5′:5,6]­indolo­[3,2-c]­quinolin-6-one (2k), which exhibited the characteristic DNA topoisomerase-I inhibitory mechanism of action with potent in vitro anticancer activity. Compound 2k actively inhibited ARC-111- and SN-38-resistant HCT-116 cells and showed in vivo activity in mice bearing human HCT-116 and SJCRH30 xenografts. The interaction of 2k with the Top–DNA cleavable complex was revealed by docking simulations to guide the future optimization of 5,11-dihydro-6H-indolo­[3,2-c]­quinolin-6-ones as topoisomerase-I inhibitors.

Subnanomolar Met inhibitors.

No abstract

In this study, we reported the inhibition profiles of 4′‐acylpyrrole–5‐fluoroindolin‐2‐one 3 with a C‐3′ side chain for VEGFR2, PDGFR‐β, and FGFR‐1 protein kinases. The pyrrole‐fused cyclohexanone moiety provided 3 with the best potency to inhibit the three kinases, and the C‐3′ side chains contributed to the different inhibition profiles of 3. Compound 3b with a C‐3′ 2‐carboxylethyl side chain showed good potency for the three kinase (IC50: 25–260 nM), and compound 3g with a N,N‐dialkyl‐2‐carbamoylethyl side chain was more active for VEGFR2 (IC50: 59 nM) and PDGFR‐β (IC50: 16 nM) than FGFR‐1 (IC50: 1.7 μM). The C‐3′ 3‐(dialkylamino)propyl side chain accomplished 3h–j as selective PDGFR‐β inhibitors (IC50: 7.8–13 nM). Compound 3b was further investigated and found potent to inhibit VEGF‐ and FGF‐dependent cell proliferation with moderate in vivo anticancer activity. Results from docking simulations revealed that the interactions of 3b with VEGFR2 and FGFR‐1 which could account for the different inhibition profiles of 3.

Globo H antigen is a hexasaccharide originally isolated as a ceramide-linked glycolipid from the human breast cancer cell line MCF-7. Globo H is also highly expressed in many other cancers such as colon cancer, ovarian cancer, gastric cancer, pancreatic cancer, lung cancer, and prostate cancer. DCBD16001 is an ADC from humanized anti-Globo H antibody DCBPR1101. DCBPR1101 and DCBD16001 both show good binding affinities against Globo H antigen. DCBD16001 also shows high cytotoxicity in Globo H overexpressing cell line MCF-7 and HCC-1428 and shows no cytotoxicity in Globo H negative cell line BT-474. DCBD16001 can internalize to target cell more than 50% within 4.0 hours. In vivo evaluation data indicates that DCBD16001 shows acceptable PK profiles and good efficacy. It shows nearly 80% tumor growth inhibition in HCC-1428 xenograft model. DCBD16001 is a candidate under pre-clinical development and expected to apply IND submission within two years. Citation Format: Wei-Ting Sun, Shih-Hsien Chuang, Chao-Pin Lee, Yi-Jen Chen, Win-Yin Wei, Ying-Shuan Lee, Chuan-Lung Hsu, Yu-Chin Nieh, Chia-Cheng Wu. Development of anti-Globo H ADC against cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 813.