Abstract
A series of novel 1-oxa-4-azaspiro[4.5]deca-6,9-diene-3,8-diones were designed and synthesized by using 4-aminophenol and α-glycolic acid or lactic acid as starting materials in three or four steps. The key step is the metal-catalyzed oxidative cyclization of the amide to 1-oxa-4-azaspiro[4.5]deca-6,9-diene-3,8-diones (10a and 10b), the reaction conditions of which are investigated and optimized. The anticancer activity of 17 1-oxa-4-azaspiro[4.5]deca-6,9-diene-3,8-dione derivatives was evaluated. Preliminary results showed that 15 compounds have moderate to potent activity against human lung cancer A549, human breast cancer MDA-MB-231, and human cervical cancer HeLa cancer cell lines. Among them, compounds 11b and 11h were the most potent against A549 cell line with 0.18 and 0.19 µM of IC50, respectively; compounds 11d, 11h, and 11k showed the most potent cytotoxicity against MDA-MB-231 cell line with 0.08, 0.08, and 0.09 µM of IC50, respectively, while the activities of 11h, 11k, and 12c against HeLa cell line were the most potent with 0.15, 0.14, and 0.14 µM of IC50, respectively. Compound 11h is a promising candidate for further development, which emerged as the most effective compound overall against the three tested cancer cell lines.
Highlights
Spirocyclic compounds are an important class of widely distributed natural products [1], such as crotonosine extracted from legumes [2] and brevione O (1) extracted from marine fungi [3]
1-Oxa-4-azaspiro[4.5]deca-6,9-diene-3,8-dione derivatives were prepared as shown in Scheme 1
1-Oxa-4-azaspiro[4.5]deca-6,9-diene-3,8-dione derivatives were prepared shown in Scheme
Summary
Spirocyclic compounds are an important class of widely distributed natural products [1], such as crotonosine extracted from legumes [2] and brevione O (1) extracted from marine fungi [3]. Many spirocycles exhibit different biological activities including antitumor activities. As shown, spirocyclic oxindole-benzofuro-azepinones (2) have potent antitumor activity comparable to cisplatin [4] and the IC50 value of 3,30 -spirocyclopentene oxindole (3) toward wild-type p53-MDM2 was 3.1 nM [5]. The compounds with a quinone scaffold are another class of interesting natural products They play an important role in the redox process of organisms due to the special character of the quinones, with potential to become attractive cancer chemotherapy drugs such as cryptotanshinone (CPT, 4), a diterpenoid which exerts antitumor activity through the inhibition of STAT3, [6] and β-lapachone (β-lap, 5), which is a quinone oxidoreductase 1 (NQO1 or NAD(P)H)-dependent antitumor drug [7,8]. Our previous work hybridized the spirocycle and quinone scaffolds to generate a novel series of 1-oxa-4-azaspiro[4.5]deca-6,9-diene-3,8-diones (6) which showed promising
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