Isolation, Characterization of Undescribed Alkaloids, and Semisynthetic Modifications of Cytotoxic Pyranoacridone Alkaloids from Glycosmis pentaphylla

Abstract

Two undescribed alkaloids (10 and 11), along with nine known alkaloids (1-9), have been isolated from the stem and root bark of Glycosmis pentaphylla. Among them are carbocristine (11), a carbazole alkaloid first time isolated from a natural source, and acridocristine (10), a pyranoacridone alkaloid first time isolated from the genus "Glycosmis". In vitro cytotoxicity of isolated compounds has been analyzed on breast cancer (MCF-7), lung cancer (CALU-3), and squamous cell carcinoma cell lines (SCC-25). The results demonstrated that compounds are moderately active. In order to study the structural activity relationship of majorly isolated compounds, semisynthetic modifications have been done on majorly isolated compounds such as des-N-methylacronycine (4) and noracronycine (1) to synthesize 11 semisynthetic derivatives (12-22) on functionalizable -NH and -OH groups of the pyranoacridone scaffold at 12th and 6th positions. Semisynthetic derivatives are explored on the same cell lines as isolated compounds, and the results exhibit that semisynthetic compounds showed potent cytotoxic activity compared with naturally isolated compounds. In the case of CALU-3, the dimer at -OH position of noracronycine (1), i.e., compound 22, showed 24-fold better activity with an IC₅₀ of 4.49 μM compared with noracronycine (1) with IC₅₀ 97.5 μM. In MCF-7, the dimer at -OH position of noracronycine (1), i.e., compound 22, showed 14-fold better activity with an IC₅₀ of 13.2 μM compared with noracronycine (1) with IC₅₀ 187 μM.

Figure 1

Structures of isolated compounds from G. pentaphylla (stem and root bark).

Figure 2

¹H–¹H COSY and ¹H–¹³C HMBC correlations of compounds 6 and 7.

Figure 3

¹H–¹H COSY, ¹H–¹³C HMBC, and ¹H–¹H NOESY correlations of compound 10 and 11.

Figure 4

General scheme for the synthesis of compounds 12–16.

Figure 5

General scheme for the synthesis of compounds 18–21.

Figure 6

Scheme for the synthesis of compound 17.

Figure 7

Scheme for the synthesis of compound 22.