Synthesis and Antiproliferative Activities of Ottelione A Analogues

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...

Enantioselective Total Synthesis of Otteliones A and B, Novel and Powerful Antitumor Agents from the Freshwater Plant Ottelia alismoides

“…It is interesting to look at the various synthetic methodologies devised for constructing the requisite bicyclic hydrindane skeleton and whole carbon framework by controlling the correct stereochemistry. These synthetic studies hold promise for preparing additional analogues of otteliones A and B with the aim of exploring their structure-activity relationships [41], which should be useful for the development of novel anticancer agents.…”

Design, synthesis, and in vitro/vivo anticancer activity of 4‐substituted 7‐(3‐fluoro‐4‐methoxybenzyl)‐7H‐pyrrolo[2,3‐d]pyrimidines

“…[ 16 ] Our group has demonstrated a radical cyclization methodology for the enantioselective total synthesis for 1 . [ 13 ] In the following study, [ 17 ] we established the structure–activity relationship of 1 using the synthetic methodology. Compound 2 , the desvinyl and fluoro analog of 1 , was generated and found 6–38‐fold more potent than 1 .…”

“…In addition, our study demonstrated that the exocyclic double bond was essential for the potency of 1 and 2 . [ 17 ] An irreversible nucleophilic 1,6‐addition would be responsible for their potency. [ 18,19 ] Although both 1 and 2 show potent in vitro activity, they might not be active in vivo due to their inherent instability in serum.…”

New Diarylheptanoids and a Hydroxylated Ottelione from Ottelia alismoides

“…For example, H-3 is a dddd in 13 rather than a ddddd as it is in 1a or 1b. Finally, in light of i) continuing interest in the ottelione family of antitumor agents [14] and ii) the fact that no Mosher analyses have been described for any structural analogs related to the otteliones, we report here the results of a study of the Mosher esters of the alcohol derived from each of (+)-ottelione A (1a) and (+)-ottelione B (1b). (Figure 6).…”

“…2.85 (2H, t, J = 7.5 Hz, H-1), 2.72 (2H, t, J = 7.5 Hz, H-2), 2.55 (2H, t, J =7.5 Hz, H-4), and 2.44 (2H, dt, J = 7.5, 7.5 Hz, H-5). See ref [18] for NMR spectral data for the corresponding bis-phenol (in methanol-d 4 (1S,3S,3aR,4S,7aS)-1-Ethenyl-1,2,3,3a,4,7a-hexahydro-3-[(3hydroxy-4-methoxyphenyl)methyl]-7-methylene-7H-indene-4-ol (14). To a solution of 1a (5 mg, 0.016 mmol) in MeOH (0.75 mL) was added CeCl 3 (6.5 mg, 0.017 mmol).…”