Cytotoxic leuconoxine-type diazaspiroindole alkaloids isolated from Cryptolepis dubia

Abstract

Two leuconoxine-type diazaspiroindole alkaloids, the known compound, (+)-melodinine E (1), and its new analogue, (+)-11-chloromelodinine E (2), were isolated from the stems of Cryptolepis dubia (Burm.f.) M.R. Almeida (Apocynaceae), collected in Laos. The chemical structures of these compounds were determined by analysis of their spectroscopic data and by comparison of these data with literature values, of which the molecular structure of 1 has been determined previously by analysis of its single-crystal X-ray diffraction data. The absolute configurations of 1 and 2 have been defined by their experimental and simulated electronic circular dichroism (ECD) spectroscopic data and supported by ¹H and ¹³C NMR-based DP4+ probability analysis and specific rotation calculations. When tested against a small panel of human cancer cell lines, these two compounds exhibited selective cytotoxicity toward OVCAR3 human ovarian cancer cells.

Keywords: Absolute configuration; Cryptolepis dubia; Leuconoxine-type diazaspiroindole alkaloids; Melodinine E; Selective cytotoxicity.

Fig. 1.

Structures of (+)-melodinine E (1) and (+)-11-chloromelodinine E (2).

Fig. 2.

COSY (, ¹H ¹H) and key HMBC (, ¹H ¹³C) (upper) and selected NOESY (, ¹H ¹H) (lower) correlations for 1 and 2.

Figure 3.

Overlaid ECD spectra of (+)-melodinine E (1) (black, left) and (+)-11-chloromelodinine E (2) (black, right), the Boltzmann-averaged ECD spectra of 1 (red, left) and 2 (red, right), and the Boltzmann-weighted ECD spectra of 5-epi-1 (green, left) and 5-epi-2 (green, right). The ECD spectra of 1 and 2 were obtained in MeOH and corrected by subtracting a spectrum of the appropriate solution in the absence of the samples recorded under identical conditions. The σ-value (artificial line broadening) was set to 0.21 and 0.23 eV for 1 and 2, respectively.

Figure 4.

Molecular orbitals involved in key transitions in the calculated ECD spectrum of the lowest-energy conformer 2 of 1 at the mPW1PW91/6–311+G(d,p) level in MeOH. Orbitals are plotted with 0.03 e−/au isovalues.