Ozoroalide, a new macrolide from Ozoroa insignis

Yonghong Liu

The crude methanol bark extract of the Zimbabwean medicinal plant, Ozoroa insignis, showed in-vitro cytotoxic activity against Hep-G2 (human hepatocellular carcinoma), MDA-MB-231 (human mammary adenocarcinoma), and 5637 (human primary bladder carcinoma). Bioactivity-directed chromatographic separation led to isolation of anacardic acid and ginkgoic acid as the cytotoxic components.

Ozoroa insignis Del. is an ethnobotanical plant widely used in traditional medicine for various ailments, including schistosomiasis, tapeworm, and hookworm infections. From the so far not investigated fruits of Ozoroa insignis, the anthelmintic principles could be isolated through bioassay-guided isolation using Caenorhabditis elegans and identified by NMR spectroscopic analysis and mass spectrometric studies. Isolated 6-[8(Z)-pentadecenyl] anacardic (1), 6-[10(Z)-heptadecenyl] anacardic acid (2), and 3-[7(Z)-pentadecenyl] phenol (3) were evaluated against the 5 parasitic organisms Schistosoma mansoni (adult and newly transformed schistosomula), Strongyloides ratti, Heligmosomoides polygyrus, Necator americanus, and Ancylostoma ceylanicum, which mainly infect humans and other mammals. Compounds 1–3 showed good activity against Schistosoma mansoni, with compound 1 showing the best activity against newly transformed schistosomula with 50% activity at 1µM. The isolated compounds were a...

Chemical stability of a new class of ozonide (1,2,4 trioxolanes) antimalarial compounds was investigated. The effects of pH, ionic strength, dielectric constant and cyclodextrin-complexation on the chemical stability and degradation product formation of selected compounds were examined. The mechanism of degradation in aqueous solution was probed using 18O-labelled water and kinetic solvent isotope effect studies. The effect of stereochemistry was investigated using selected pairs of stereoisomers. The degradation of the ozonides in aqueous solution followed apparent first-order kinetics, with no effect of ionic strength and no indication of any direct involvement of water in the degradation mechanism. All major degradation products were identified and mass balance was confirmed. Stereochemistry had a significant effect on degradation rate; trans isomers degrading approximately four-fold faster than the corresponding cis isomers. The degradation rates were essentially independent of pH above pH 2; however, an additional specific acid catalysed pathway was dominant below pH 2. Solvent dielectric constant had a significant effect on the degradation rate. It is proposed that the degradation observed in aqueous solution occurred through a concerted heterolytic scission of the central ozonide ring, with chemical substituents on the cyclohexyl ring having only a minor influence on degradation rate. © 2006 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 95:737–747, 2006

Fitoterapia 78 (2007) 388 – 389 www.elsevier.com/locate/fitote Phythochemical communication Ozoroalide, a new macrolide from Ozoroa insignis Pedro J.M. Abreu a,⁎, Yonghong Liu a,b b a REQUIMTE, Departamento de Química, FCT-UNL, 2829-516, Caparica, Portugal Guangdong Key Laboratory of Marine Materia Medica, South China Sea Institute of Oceanology, Chinese Academy of Sciences, Guangzhou 510-301, PR China Received 21 July 2005; accepted 5 April 2007 Available online 5 May 2007 Abstract From the roots of Ozoroa insignis a new orsellinic acid named ozoroalide (1) and anacardic acid methyl ester (2) were isolated and identified on the basis of spectroscopic methods. © 2007 Elsevier B.V. All rights reserved. Keywords: Ozoroa insignis; Ozoroalide; Anacardic acid methyl ester 1. Plant Ozoroa insignis Del. (Heeria insignis Del.) (Anacardiaceae), collected in January 1994 at Contuboel, Guinea-Bissau was identified in the Herbarium of Botany Centre (LISC), where a voucher specimen is deposited. 2. Uses in traditional medicine Roots are used as a remedy for diarrhea, venereal diseases, tapeworm and hookworm, schistosomiasis, kidney trouble, migraine, and malaria [1–7]. The leaves like the roots have purgative action [6]. Poultices of pulped leaves are used for swellings on the feet, and a paste of leaves and bark to treat to skin-diseases [6]. In Guinea-Bissau, the infusion of roots is taken by women after childbirth to increase lactation [8]. In addition, anthelmintic effect of root bark and leaves against the worms Schistosoma mansoni and Hymenolepis diminuta [4], cytotoxic activity of a bark extract against Hep-G2, MDA-MB-231, and 5637 human cancer cell lines [1], and in vitro topoisomerase inhibition of stembark and stemwood [9], have been reported. 3. Previously isolated constituents Ginkgolic acid [1], anacardic acid [5], and essential oils [10]. 4. New isolated constituents 25 Ozoroalide (1, Fig. 1), (yield: 13 mg from 1.65 kg of dried roots), light yellow solid, mp 188-189 °C; [α]D + 5.2° (c 25 1.3 CHCl3); [α]365 − 63.3 (c 0.3 CHCl3); UV max (EtOH): 207 (log ε 3.85), 249 (3.09), 283 (2.94) nm; IR bands ⁎ Corresponding author. Fax: +351 212948550. E-mail address: pma@dq.fct.unl.pt (P.J.M. Abreu). 0367-326X/$ - see front matter © 2007 Elsevier B.V. All rights reserved. doi:10.1016/j.fitote.2007.04.001 P.J.M. Abreu, Y. Liu / Fitoterapia 78 (2007) 388–389 389 Fig. 1. Structure of compounds 1 and 2. (NaCl): 3364, 1686, 1606, 1280 cm− 1; HRESIMS: m/z 293.1740 [M + H]+. Calc. for C17H25O4 293.1747.EIMS m/z: 292 [M]+(70), 181 (100), 176 (65), 137 (65), 83 (25). 1H-NMR (400 MHz, CDCl3): δ 1.26 (1H, m, H-7a), 1.31 (3H, d, 6.4 Hz, H-17), 1.32 (1H, m, H-8a), 1.40 (1H, m, H-6a), 1.41 (1H, m, H-5a), 1.47 (1H, m, H-7b), 1.48 (1H, m, H-8b), 1.54 (1H, m, H-6b), 1.61 (1H, m, H-4a), 1.64 (2H, m, H-9a, H-9b), 1.67 (1H, m, H-5b), 1.90 (1H, m, H-4b), 2.46 (1H, ddd, J 13.4, 6.7, 6.7 Hz, H-10a), 2.64 (1H, ddd, J 13.4, 6.7, 6.7 Hz, H-10b), 3.70 (3H, s, OCH3), 5.27 (1H, m, H-3), 6.21 (1H, s, H-14), 6.22 (1H, s, H-12); 13C NMR (100.61 MHz, CDCl3): δ 19.5 (C-17), 21.3 (C-5), 24.2 (C-6), 25.5 (C-7), 26.4 (C-8), 30.0 (C-9), 30.4 (C-10), 32.3 (C-4), 55.8 (OCH3), 72.4 (C-3), 97.0 (C-14), 108.3 (C-12), 117.3 (C16), 143.0 (C-11), 157.7 (C-15), 157.9 (C-13), 169.1 (C-1); HMBC (key H → C correlations): OCH3 → C-13; H10 → C-9, C-11, C-12, C-16; H-12 → C-10, C-16; H-14 → C-12, C-15, C-16; NOESY (key H ↔ H correlations): OCH3 ↔ H-12, H-14; H-12 ↔ H-10a. Anacardic acid methyl ester (2, Fig. 1): (yield: 50 mg from 1.65 kg of dried roots), white solid, mp 38–39 °C; UV max (EtOH): 210 (log ε 6.72), 245 (6.05), 311 (5.76) nm; IR bands (NaCl): 3064, 2917, 2852, 1665, 1607, 1578, 1449, 1315, 1250, 1205 cm− 1; EIMS m/z: 362 [M]+(83), (C23H38O3); 330 (48), 312 (40), 166 (63), 161 (74), 149 (100); 1H-NMR (400 MHz, CDCl3): δ 0.89 (3H, m, 15′-Me), 1.26 (24H, m, H-3′ to H-14′), 1.53 (1H, m, H-2′), 2.88 (1H, m, H-1′), 3.96 (3H, s, OCH3), 6.72 (1H, d, 7.2 Hz, H-4), 6.85 (1H, d, 8.4 Hz, H-6), 7.29 (1H, dd, 8.4, 7.2 Hz, H-5); 13C NMR (100.61 MHz, CDCl3): δ 14.1 (15′-CH3), 22.7 (C-14′), 27.2, 29.4, 29.5, 29.7, 29.9, 31.7 (C-3′ to C-13′), 31.9 (C-2′), 36.4 (C-1′), 52.1 (OCH3), 111.9 (C-2), 115.6 (C-6), 122.4 (C-4), 134.2 (C-5), 146.2 (C-3), 162.6 (C-1), 172.0 (CO); HMBC (key H → C correlations): OCH3 → CO; H-1′ → C-2, C-3, C-4; H-4 → C-1′, C-2; H-6 → C-1, C-4; NOESY (key H ↔ H correlations): H-4 ↔ H-1′, H-2′; H-5 ↔ H-4, H-6. Acknowledgment Fundação para a Ciência e a Tecnologia for a post-doc. grant (SFRH/BPD/14656/2003). References [1] [2] [3] [4] [5] [6] [7] [8] [9] [10] Rea AI, Schmidt M, Setzer WN, Sibanda S, Taylor C, Gwebu ET. Fitoterapia 2003;74:732. Gelfand M, Mavi S, Drummond RB, Ndemera B. The Traditional Medical Practitioner in Zimbabwe. Mambo Press; 1985. Ndamba J, Nyazema N, Makaza N, Anderson C, Kaondera KC. J Ethnopharmacol 1994;42:125. Mølgaard P, Nielsen SB, Rasmussen DE, Drummond RB, Makaza N, Andreassen J. J Ethnopharmacol 2001;74:257. He W, Puyvelde LV, Bosselaers J, de Kimpe ND, Flaas MVD, Roymans A, et al. Pharm Biol 2002;40:74. Burkill HM. The useful plants of West Tropical Africa, vol. 1. Kew: Royal Botanic Gardens; 1985. Asase A, Oteng-Yeboah AA, Odamtten GT, Simmonds MSJ. J Ethnopharmacol 2005;99:273. Abreu PM, Martins ES, Kayser O, Bindseil K-U, Siems K, Seemann A, et al. Phytomedicine 1999;6:187. Wall ME, Wani MC, Brown DM, Fullas F, Olwald JB, Josephson FF, et al. Phytomedicine 1996;3:281. Ayedoun MA, Moudachirou M, Garneau F-X, Gagnon H, Jean F-I, Tomi F, et al. J Essent Oil Res 1998;10:529.

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Ozoroalide, a new macrolide from Ozoroa insignis

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