Enantioselective Total Synthesis of Otteliones A and B

Chen, Cheng‐Hui; Sha, Chin-Kang

doi:10.1021/ol902776d

Cited by 25 publications

(25 citation statements)

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“…Compound 4 and its C-1 desvinyl derivative 11a, C-7 methylene derivative 19, and C-7 exocyclic ethylidene derivative 23 were assayed first (Table 1). Enantiomerically pure 4, prepared according to our published method, 21 showed strong inhibition of the growth of the cancer cells with IC 50 values of 0.40−92.8 nM; the results are consistent with the reported potency of 4 from natural 12 and synthetic sources. 17 The cells most sensitive toward 4 were HCT-116 and A375 cells, which were inhibited at subnanomolar concentrations (IC 50 , 0.74 and 0.40 nM, respectively).…”

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confidence: 87%

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Synthesis and Antiproliferative Activities of Ottelione A Analogues

Chang

Wei

et al. 2012

ACS Med. Chem. Lett.

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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...

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“…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.…”

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Synthesis and Antiproliferative Activities of Ottelione A Analogues

Chang

Wei

et al. 2012

ACS Med. Chem. Lett.

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“…Synthetic strategy: Sha et al reported the fourth total synthesis of (+)-1 and (−)-2 in 2010 [20]. Their retrosynthetic analysis is illustrated in Scheme 14.…”

Section: Sha's Total Synthesismentioning

confidence: 99%

“…In the following year, Mehta and our groups independently achieved the first enantioselective total synthesis of naturally occurring (+)-1 and (−)-2, leading to the establishment of their absolute configurations [15][16][17]. Recently, two additional total syntheses of (+)-1 and (−)-2 were reported by Clive et al in 2007 [18,19] and Sha et al in 2010 [20], respectively. In addition, the formal total synthesis of (+)-1 and (−)-2 was also reported by Ryu et al in 2008 [21].…”

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confidence: 99%