A Novel ent-Kaurane Diterpenoid from the Croton tonkinensis GAGNEP

Abstract

Croton tonkinensis GAGNEP belonging to Euphobiaceae grows wildly in Vietnam, and the leaves of this plant are prescribed for stomachache. 1) The crude drug from the leaves was previously shown to have an inhibitory effect on malaria parasites. 2) Later, Phan et al. 3) reported the isolation and structural elucidation of a new ent-kaurane diterpenoid, ent7b-hydroxy-15-oxokaur-16-en-18-yl acetate from the leaves. In the course of our investigation of the biologically active compounds from Vietnamese medicinal plants, we reinvestigated the chemical constituents of the leaves of C. tonkinensis and isolated six alkaloids. 4) Recently, we collected a large amount of the leaves and isolated a novel ent-kaurane-type diterpenoid (1). This paper describes the isolation and structural characterization of compound 1.Compound 1 was obtained as white needles, [a] D 20 Ϫ96.0°( cϭ0.80, CH 3 OH). The molecular formula was determined to be C 22 H 32 O 5 by high resolution electron impact (HR-EI)-MS. Its IR and UV spectra indicated the presence of a hydroxyl group (3272 cm Ϫ1 ), a double bond (1651 cm Ϫ1 ), an acetyl group (1727, 1243 cm Ϫ1 ), 3) and an absorption maximum at 230 nm, respectively. The 1 H-NMR spectrum of 1 (Table 1) showed the presence of three methyl groups, two exo-methylene protons and two hydroxyl groups. The 13 C-NMR spectrum of 1 (Table 1) showed resonances for 22 carbons including one conjugated ketone (d 207.1), an acetyl group (d 21.0, 169.7), a methine (d 72.3) bearing an acetoxyl group, an exo-methylene (d 116.8, 148.3), five methylenes and three quaternary carbons. The NMR spectral data of compound 1 were similar to those of ent-1a,11a-diacetoxy7b,14a-dihydroxy-kaur-16-en-15-on (rastronol A), 5) suggesting that compound 1 was a kaurane-type diterpenoid. The position of an acetyl group was determined at C-1 due to a long-range correlation between this group and H-1 in the heteronuclear multiple bond connectivity (HMBC) spectrum. 6) Further, two hydroxyl groups were determined at C-7 and C-14, respectively, by HMBC correlation between 7-OH and C-7 as well as the 14-OH and C-13, C-14 and C-15 in the HMBC spectrum. The stereochemistry of 1 was determined by nuclear Overhauser effect spectroscopy (NOESY) spectrum (Table 1), in which the NOEs were observed between (1) H-5 and H-9, H-18; (2) H-7 and H-5, H-9; (3) H-1 and H-19, H-20; (4) H-14 and H-13, H-20 indicating that H-5, H-7, H-9, H-18, 1-OAc and 14-OH were axial, and H-1, H-13, H-19, H-20 and 7-OH were equatorial.Acetylation of 1 with acetic anhydride in pyridine yielded a triacetate (2) with the molecular formula of C 26 H 36 O 7 by HR-EI-MS. The IR spectrum of 2 was similar to that of 1 except for the absence of absorption of the hydroxyl group. The A novel ent-kaurane diterpenoid, ent-1a a-acetoxy-7b b,14a a-dihydroxy-kaur-16-en-15-on has been isolated from leaves of Croton tonkinensis GAGNEP. Its structure was determined by a combination of spectroscopy, X-ray crystallographic analysis and the chemical reaction acetylation.

Traditional uses, chemistry and pharmacology of Croton species (Euphorbiaceae)

“…3 C. tonkinensis, a species native in Vietnam, has been a prolific source of ent-kauranetype diterpenoids. From leaves of this species ent-7β-hydroxy-15-oxokaur-16-en-18-yl acetate 63 and ent-1α-acetoxy-7β,14α-dihydroxy-kaur-16-en-15-one 64 45 although it may be found also in the leaf chloroplasts of C. stellatopilosus Ohba. 67 C. oblongifolius has been a prolific source of diterpenoids, including: (i) the clerodane 11-dehydro (-) hardwickiic acid; 68 (ii) the labdanes labda-7,12(E),14-triene, labda-7,12(E),14-triene-17-al, labda-7,12(E),14-triene-17-ol, labda-7,12(E),14-triene-17-oic acid; 69 (iii) the cembranoid diterpenes crotocembranoic acid and neocrotocembranal 70 (6); (iv) the cytotoxic labdane diterpenoids 2-acetoxy-3-hydroxy-labda-8(17),12(E)-14-triene, 3-acetoxy-2-hydroxy-labda-8(17),12(E)-14-triene, and 2,3-dihydroxy-labda-8(17),12(E),14-triene were also isolated from the stem bark of C. oblongifolius; 71 (v) the labdane nidorellol, the furoclerodane croblongifolin and the clerodane crovatin; 72 (vi) the kaurane (-)ent-kaur-16-en-19-oic acid; 40 (vii) the halimanes crotohalimaneic acid (7), crotohalimoneic acid and 12-benzoyloxycrotohalimaneic acid; 73 (viii) new labdane-type diterpenoids 3-oxygenated ent-manoyl oxide derivatives with a 8,13-epoxytricyclic ring system and hydroxylabdandienes.…”

Effects of Substituents on Ch Bond Dissociation Enthalpies of Ent-Kaurane Diterpenoids: A DFT Study

“…Its leaves have been used to treat burns (boils), abscesses, impetigo, abdominal pain, dyspepsia, gastric and duodenal ulcers [2], stomachache as well as to cure malaria paradise, urticarial, leprosy, psoriasis and genital organ prolapse [1][2][3][4]. Phytochemical investigations on C. tonkinensis have shown the presence of benzoic acid, sterols, long-chain alkyl alcohols, flavonoid glucosides [5] and ent-kaurane diterpenoids [6][7][8][9][10][11][12][13]. Recently, several studies revealed that the presence of ent-kaurane diterpenoids was correlated to toxicity [11] anti-inflammatory and cancel chemo-preventive activities [9,16], which prompted us to continuously investigate the antioxidant potential of these phytochemical constituents.…”

“…In this study, the CH bond dissociation enthalpies (BDEs) of seven ent-kaurane diterpenoids extracted from Croton tonkinensis Gagnep including: ent-18-acetoxy-7hydroxykaur-16-en-15-one (1) [15,16], ent-1α-acetoxy-7,14α-dihydroxykaur-16-en-15-one (2) [7,9], ent-16(S)-18-acetoxy-7-hydroxykaur-15-one (3) [10,16], ent-7,14α-dihydroxykaur-16en-15-one (4) [9,17], ent-18α-acetoxy-7α,14-dihydroxykaur-16-en-15-one (5) [9], ent-1α,14αdiacetoxy-7-hydroxykaur-16-en-15-one (6) [10], ent-1α,7-diacetoxy-14α-hydroxykaur-16-en-15-one (7) [10] compounds ( Figure 1) are systematically calculated at M05-2X/6-31+G(d) level of theory in order to evaluated the antioxidant potential via hydrogen atom transfer (HAT) mechanism. In addition, the effects of different substituents such as -NH 2 , -OH, -NO 2 , -SH, -CN, -Cl, -CONH 2 , -CH-(CH 3 ) 2 , -NHCOCH 3 , -OCOCH 3 and -C 2 H 5 on BDE values will be investigated in the attempt to ameliorate their antioxidant activity.…”

Cytotoxic, apoptotic, and sensitization properties of ent‐kaurane‐type diterpenoids from Croton tonkinensis Gagnep on human liver cancer HepG2 and Hep3b cell lines

“…It has been used commonly in traditional prescription to treat leprosy, psoriasis, malaria, and genital organ prolapse . E nt‐ kaurane‐type diterpenoids were isolated from the leaves of Croton tonkinensis Gagnep, and their structure determined from phytochemical investigations . For some of them, the cytotoxic properties have been tested against breast MCF‐7, lung A549 , liver SK‐HEP1 , intestinal CaCo‐2, and colon LS180 cancer cell lines.…”