Herpecaudin from Herpetospermum caudigerum, a Xanthine Oxidase Inhibitor with a Novel Isoprenoid Scaffold^[*]

Abstract

Herpecaudin (3), a xanthine oxidase inhibitor with an unprecedented scaffold, was discovered from Herpetospermum caudigerum seeds. The structure was determined by spectroscopic and X-ray single crystallographic methods. A possible biogenetic pathway leading to herpecaudin is proposed, starting from congeners 23,24-dihydrocucurbitacin E (1) and endecaphyllacin B (2), and involving retro-aldol cleavage as a key step. All three compounds proved to be active and represent new scaffolds of non-purine analogue xanthine oxidase inhibitors.

Key words

Herpetospermum caudigerum - Cucurbitaceae - Herpecaudin - xanthine oxidase inhibitor - retro-aldol reaction - cucurbitane-type terpenoid

^* Dedicated to Professor Dr. Dr. h. c. mult. Kurt Hostettmann in recognition of his outstanding contribution to natural product research.

^** These authors contributed equally to this work.

• References

• 1 Lin X, Zhao C, Qin A, Hong D, Liu W, Huang K, Mo J, Yu H, Wu S, Fan S. Association between serum uric acid and bone health in general population: a large and multicentre study. Oncotarget 2015; 6: 35395-35403
• 2 Li X, Song P, Li J, Wang P, Li G. Relationship between hyperuricemia and dietary risk factors in Chinese adults: a cross-sectional study. Rheumatol Int 2015; 35: 2079-2089
• 3 Teng GG, Pan A, Yuan JM, Koh WP. Food sources of protein and risk of incident gout in the singapore Chinese health study. Arthritis Rheumatol 2015; 67: 1933-1942
• 4 Kuo CC, Weaver V, Fadrowski JJ, Lin YS, Guallar E, Navas-Acien A. Arsenic exposure, hyperuricemia, and gout in US adults. Environ Int 2015; 76: 32-40
• 5 Richette P, Garay R. Novel drug discovery strategies for gout. Expert Opin Drug Discov 2013; 8: 183-189
• 6 Schlesinger N. Difficult-to-treat gouty arthritis a disease warranting better management. Drugs 2011; 71: 1413-1439
• 7 Xu C, Wan X, Xu L, Weng H, Yan M, Miao M, Sun Y, Xu G, Dooley S, Li Y, Yu C. Xanthine oxidase in non-alcoholic fatty liver disease and hyperuricemia: One stone hits two birds. J Hepatol 2015; 62: 1412-1419
• 8 Roncal-Jimenez C, García-Trabanino R, Barregard L, Lanaspa MA, Wesseling C, Harra T, Aragón A, Grases F, Jarquin ER, González MA, Weiss I, Glaser J, Sánchez-Lozada LG, Johnson RJ. Heat stress nephropathy from exercise-induced uric acid crystalluria: A perspective on mesoamerican nephropathy. Am J Kidney Dis 2016; 67: 20-30
• 9 Yadav D, Lee ES, Kim HM, Choi E, Lee EY, Lim JS, Ahn SV, Koh SB, Chung CH. Prospective study of serum uric acid levels and incident metabolic syndrome in a Korean rural cohort. Atherosclerosis 2015; 241: 271-277
• 10 Braga F, Pasqualetti S, Ferraro S, Panteghini M. Hyperuricemia as risk factor for coronary heart disease incidence and mortality in the general population: a systematic review and meta-analysis. Clin Chem Lab Med 2016; 54: 7-15
• 11 Mantovani A, Rigolon R, Pichiri I, Pernigo M, Bergamini C, Zoppini G, Bonora E, Targher G. Hyperuricemia is associated with an increased prevalence of atrial fibrillation in hospitalized patients with type 2 diabetes. J Endocrinol Invest 2016; 39: 159-167
• 12 Pacher P, Nivorozhkin A, Szabo C. Therapeutic effects of xanthine oxidase inhibitors: renaissance half a century after the discovery of allopurinol. Pharmacol Rev 2006; 58: 87-114
• 13 Carnovale C, Venegoni M, Clementi E. Allopurinol overuse in asymptomatic hyperuricemia a teachable moment. JAMA Intern Med 2014; 174: 1031-1032
• 14 Bach MH, Simkin PA. Uricosuric drugs: the once and future therapy for hyperuricemia?. Curr Opin Rheumatol 2014; 26: 169-175
• 15 Shen B, Chen H, Shen C, Xu P, Li J, Shen G, Yuan H, Han J. Hepatoprotective effects of lignans extract from Herpetospermum caudigerum against CCl₄-induced acute liver injury in mice. J Ethnopharmacol 2015; 164: 46-52
• 16 Yuan HL, Yang M, Li XY, You RH, Liu Y, Zhu J, Xie H, Xiao XH. Hepatitis B virus inhibiting constituents from Herpetospermum caudigerum . Chem Pharm Bull (Tokyo) 2006; 54: 1592-1594
• 17 Zhang M, Deng Y, Zhang HB, Su XL, Chen HL, Yu T, Guo P. Two new coumarins from Herpetospermum caudigerum . Chem Pharm Bull (Tokyo) 2008; 56: 192-193
• 18 Yu JQ, Hang W, Duan WJ, Wang X, Wang DJ, Qin XM. Two new anti-HBV lignans from Herpetospermum caudigerum . Phytochem Lett 2014; 10: 230-234
• 19 Yang F, Zhang HJ, Zhang YY, Chen WS, Yuan HL, Lin HW. A hepatitis B virus inhibitory neolignan from Herpetospermum caudigerum . Chem Pharm Bull (Tokyo) 2010; 58: 402-404
• 20 Chen JC, Zhang GH, Zhang ZQ, Qiu MH, Zheng YT, Yang LM, Yu KB. Octanorcucurbitane and cucurbitane triterpenoids from the tubers of Hemsleya endecaphylla with HIV-1 inhibitory activity. J Nat Prod 2008; 71: 153-155
• 21 Kanchanapoom T, Kasai R, Yamasaki K. Cucurbitane, hexanorcucurbitane and octanorcucurbitane glycosides from fruits of Trichosanthes tricuspidata . Phytochemistry 2002; 59: 215-228
• 22 Afifi MS, Ross SA, ElSohly MA, Naeem ZE, Halaweish FT. Cucurbitacins of Cucumis prophetarum and Cucumis prophetarum . J Chem Ecol 1999; 25: 847-859
• 23 Zhang YL, Zhang J, Jiang N, Lu YH, Wang L, Xu SH, Wang W, Zhang GF, Xu Q, Ge HM, Ma J, Song YC, Tan RX. Immunosuppressive polyketides from mantis-associated Daldinia eschscholzii . J Am Chem Soc 2011; 133: 5931-5940
• 24 Tian Y, Jiang N, Zhang AH, Chen CJ, Deng XZ, Zhang WJ, Tan RX. Muta-mycosynthesis of naphthalene analogs. Org Lett 2015; 17: 1457-1460
• 25 Longhi G, Castiglioni E, Abbate S, Lebon F, Lightner DA. Experimental and calculated CPL spectra and related spectroscopic data of camphor and other simple chiral bicyclic ketones. Chirality 2013; 25: 589-599
• 26 Frelek J, Butkiewicz A, Gorecki M, Wojcieszczyk RK, Luboradzki R, Kwit M, Rode MF, Szczepek WJ. Structure – chiroptical properties relationship of cisoid enones with an α-methylenecyclopentanone unit. RSC Adv 2014; 4: 43977-43993
• 27 Frelek J, Szczepek WJ, Weiss HP. Circular-dichroism of steroidal and related cisoid alpha,beta-unsaturated ketones. 2. Tetrahedron: Asymmetry 1995; 6: 1419-1430
• 28 Garrabou X, Beck T, Hilvert D. A promiscuous de novo retro-aldolase catalyzes asymmetric Michael additions via Schiff base intermediates. Angew Chem Int Ed Engl 2015; 54: 5609-5612
• 29 Jiang L, Althoff EA, Clemente FR, Doyle L, Rothlisberger D, Zanghellini A, Gallaher JL, Betker JL, Tanaka F, Barbas 3rd CF, Hilvert D, Houk KN, Stoddard BL, Baker D. De novo computational design of retro-aldol enzymes. Science 2008; 319: 1387-1391
• 30 Orazov M, Davis ME. Tandem catalysis for the production of alkyl lactates from ketohexoses at moderate temperatures. Proc Natl Acad Sci U S A 2015; 112: 11777-11782
• 31 Oja T, Klika KD, Appassamy L, Sinkkonen J, Mantsala P, Niemi J, Metsa-Ketela M. Biosynthetic pathway toward carbohydrate-like moieties of alnumycins contains unusual steps for C-C bond formation and cleavage. Proc Natl Acad Sci U S A 2012; 109: 6024-6029
• 32 Pojer F, Li SM, Heide L. Molecular cloning and sequence analysis of the clorobiocin biosynthetic gene cluster: new insights into the biosynthesis of aminocoumarin antibiotics. Microbiology 2002; 148: 3901-3911
• 33 Chen HW, Walsh CT. Coumarin formation in novobiocin biosynthesis: beta-hydroxylation of the aminoacyl enzyme tyrosyl-S-NovH by a cytochrome P450 NovI. Chem Biol 2001; 8: 301-312
• 34 Van Hoorn DEC, Nijveldt RJ, Van Leeuwen PAM, Hofman Z, MʼRabet L, De Bont DBA, Van Norren K. Accurate prediction of xanthine oxidase inhibition based on the structure of flavonoids. Eur J Pharmacol 2002; 451: 111-118
• 35 Diaz-Torne C, Perez-Herrero N, Perez-Ruiz F. New medications in development for the treatment of hyperuricemia of gout. Curr Opin Rheumatol 2015; 27: 164-169
• 36 Lin S, Zhang G, Liao Y, Pan J, Gong D. Dietary flavonoids as xanthine oxidase inhibitors: structure-affinity and structure-activity relationships. J Agric Food Chem 2015; 63: 7784-7794
• 37 Nguyen MTT, Awale S, Tezuka Y, Ueda JY, Le Tran Q, Kadota S. Xanthine oxidase inhibitors from the flowers of Chrysanthemum sinense . Planta Med 2006; 72: 46-51
• 38 Wang S, Li Y, Song X, Wang X, Zhao C, Chen A, Yang P. Febuxostat pretreatment attenuates myocardial ischemia/reperfusion injury via mitochondrial apoptosis. J Transl Med 2015; 13: 209
• 39 Smelcerovic Z, Veljkovic A, Kocic G, Yancheva D, Petronijevic Z, Anderluh M, Smelcerovic A. Xanthine oxidase inhibitory properties and anti-inflammatory activity of 2-amino-5-alkylidene-thiazol-4-ones. Chem Biol Interact 2015; 229: 73-81
• 40 Lin CN, Huang AM, Lin KW, Hour TC, Ko HH, Yang SC, Pu YS. Xanthine oxidase inhibitory terpenoids of Amentotaxus formosana protect cisplatin-induced cell death by reducing reactive oxygen species (ROS) in normal human urothelial and bladder cancer cells. Phytochemistry 2010; 71: 2140-2146
• 41 Xu F, Zhao X, Yang L, Wang X, Zhao J. A new cycloartane-type triterpenoid saponin xanthine oxidase inhibitor from Homonoia riparia Lour. Molecules 2014; 19: 13422-13431
• 42 Lin KW, Huang AM, Tu HY, Lee LY, Wu CC, Hour TC, Yang SC, Pu YS, Lin CN. Xanthine oxidase inhibitory triterpenoid and phloroglucinol from guttiferaceous plants inhibit growth and induced apoptosis in human NTUB1 cells through a ROS-dependent mechanism. J Agric Food Chem 2011; 59: 407-414
• 43 Nkanwen ERS, Gojayev AS, Wabo HK, Bankeu JJK, Iqbal MC, Guliyev AA, Tane P. Lanostane-type triterpenoid and steroid from the stem bark of Klainedoxa gabonensis . Fitoterapia 2013; 86: 108-114
• 44 Burns CM, Wortmann RL. Gout therapeutics: new drugs for an old disease. Lancet 2011; 377: 165-177
• 45 Menicagli R, Samaritani S, Signore G, Vaglini F, Dalla Via L. In vitro cytotoxic activities of 2-alkyl-4,6-diheteroalkyl-1,3,5-triazines: new molecules in anticancer research. J Med Chem 2004; 47: 4649-4652