Antimalarial and Antiproliferative Cassane Diterpenes of Caesalpinia sappan

Abstract

Bioassay-guided fractionation of a methanol extract of the seeds of Caesalpinia sappan led to the isolation of 12 new cassane-type diterpenes, caesalsappanins A-L (1-12). Their structures were elucidated on the basis of NMR and HRESIMS analysis, and the absolute configuration of compound 1 was determined by single-crystal X-ray crystallography. All isolated compounds were tested against a chloroquine-resistant Plasmodium falciparum strain for antiplasmodial activities and against a small panel of human cancer cell lines for antiproliferative activities. Compounds 7 and 8 displayed antimalarial activity against the chloroquine-resistant K1 strain of P. falciparum with IC50 values of 0.78 and 0.52 μM and selectivity indices of 17.6 and 16.4, respectively. Compound 10 showed antiproliferative activity against the KB cancer cell line with an IC50 value of 7.4 μM.

New Cassane Diterpenoids from <em>Caesalpinia sappan</em> and Their Antiplasmodial Activity

“…Compound 1 is representative of a new cassane diterpenoid lactone-type skeleton with an N bridge between C-19 and C-20. The 1 H and 13 C NMR data displayed a cassane diterpene skeleton with an oxygen bridge between C-19 and C-20, which was very similar to the reported compound caesalsappanin H [3]. In fact, the only difference between them was that the methoxy group at C-20 in caesalsappanin H was replaced with a butoxy group in 2.…”

“…The overall 1 H and 13 C NMR spectroscopic data confirmed that 1 is an oxynitride diterpene possessing a fused butenolide unit [9,10], and its entire structure was connected, as confirmed using HSQC, HMBC, and 1 H-1 H-COSY spectra ( Figure 2 showed that the hydroxyl group was β-oriented at C-20, and the methyl group at C-14 and the ethoxy group at C-12 were all α-oriented. The same carbon skeleton with the trans/anti/trans system of three six-membered rings A, B, and C, and the oriented proton at C-8 was β-axial and the oriented protons at C-5/C-9 was α-axial, which are well established on all cassane diterpenes isolated so far from the genus Caesalpinia [3,8,11]. Considering the biosynthetic relationship and comparing with the literature of cassane diterpenoids [12], the absolute configurations of the chiral carbons were determined to be 4S, 5R, 8S, 9S, 10S, 12S, 14R in 1 and are shown in Figure 2.…”

“…Compound 1 exhibited active antiplasmodial activity in vitro with IC50 at 3.60 μM. In addition, the compounds that we had reported also showed antiplasmodial activities; caesalsappanins A, G, H, and I displayed antiplasmodial activities with IC50 values of 7.4, 0.78, 0.52, and 2.5 μM, respectively [3]. Therefore, we believe that this plant is an important source for the diverse structure of cassane-type diterpenoids and should be further investigated for the antiplasmodial activity.…”

“…Previous phytochemical investigations indicated that this genus contains an abundant source of cassane diterpenes with different structure types, and most of them showed in vitro or in vivo pharmacological impacts such as antiproliferative [1][2][3], antiplasmodial [4][5], antibacterial [6], antihelmintic, and antineoplastic activity [7]. As a continuation of our project towards new bioactive diterpenes discovery from the genus Caesalpinia [2][3]8], we examined the chemical constituents of C. sappan and obtained two new cassane diterpenes, designated caesalsappanin R (1) and caesalsappanin S (2) (Figure 1). Compound 1 is a rather unusual cassane diterpenoid lactone-type skeleton, consisting of an N bridge between C-19 and C-20.…”

Cytotoxic and Pro-Apoptotic Effects of Cassane Diterpenoids from the Seeds of Caesalpinia sappan in Cancer Cells

“…The heartwood has been used in folk medicines as a blood tonic, expectorant, and has exhibited a wide range of activities, including anti-inflammation [7], anti-influenza virus [8], anti-allergy [9], anti-oxidation [10] and immunomodulation [11]. Previous phytochemical investigations on the seeds of C. sappan have led to isolation of a series of cassane-type diterpenoids with potent cytotoxic effect [12][13][14][15][16][17].…”