Two‐stage Regioselective Access to Non‐symmetric 3,5‐Diarylisoxazoles: Synthesis of Combretastatin A‐4 analogues

Abstract

A new two-stage regioselective access to nonsymmetric 3,5-diarylisoxazoles starting from readily available 2-aryl-1,1-dibromocyclopropanes is developed. The strategy based on the nitrosation/Suzuki arylation sequence ensures good yields of the products and a wide scope of substituents in both aryl rings. Using this strategy, a panel of combretastatin A-4 (CA-4) analogues presented by 3,5-diarylisoxazole structural motif was synthesized and evaluated for their biological activity[a] G.

Synthesis of Hybrid Isoxazole‐triazole Compounds as Potential Antiproliferative Agents

“…Isoxazole V (Figure 2), closely related to CA-4, exhibited the highest cytotoxicity and showed high selectivity towards the fast-dividing tumor cell lines A549 and MCF7 in comparison with the cell line VA13 of non-cancerous etiology. [21] Regioselective formation of 3-aryl-5-chloroisoxazoles 1,2 was accomplished conveniently by the nitrosation reaction of the corresponding 2-aryl-1,1-dichlorocyclopropanes with nitrosonium chlorosulphate using the procedure published elsewhere. [21] Subsequent dechlorination with Bu 4 NBH 4 afforded isoxazoles 3,4.…”

“…[21] Regioselective formation of 3-aryl-5-chloroisoxazoles 1,2 was accomplished conveniently by the nitrosation reaction of the corresponding 2-aryl-1,1-dichlorocyclopropanes with nitrosonium chlorosulphate using the procedure published elsewhere. [21] Subsequent dechlorination with Bu 4 NBH 4 afforded isoxazoles 3,4. [34] Isoxazoles 5,6 bearing nitro group in the benzene ring were obtained via nitrile oxide synthesis with TMS-acetylene as a dipolarophile.…”

“…The synthesized isoxazole-triazole hybrids (17)(18)(19)(20)(21)(22)(23)(24)(25)(26) were tested for cytotoxicity against the MCF7 (human breast adenocarcinoma cell line), A549 (human lung carcinoma), HEK293T (modified human embryonic kidney cells), and VA13 (healthy dividing cells of the human embryonic lung) cell lines by the standard MTT method. [43] Table 2 lists cytotoxic concentration values (CC 50 ).…”

“…It was also mentioned elsewhere [33] that replacement of the phenolic hydroxyl group in CA‐4 with an amino group resulted in a marked increase in water solubility and in vivo antitumor activity against murine solid tumors. Isoxazole V (Figure 2), closely related to CA‐4, exhibited the highest cytotoxicity and showed high selectivity towards the fast‐dividing tumor cell lines A549 and MCF7 in comparison with the cell line VA13 of non‐cancerous etiology [21] …”

“…In a previous work [21] we synthesized a panel of CA‐4 analogs presented by a 3,5‐diarylisoxazole structural motif and evaluated them for their biological activity. Some of the synthesized compounds exhibited noticeable cytotoxicity for A549, MCF7 cell lines and the lead‐compound V (Figure 2) showed toxicity in the nanomolar range and high selectivity for tumor cell lines.…”