• Xiaohua Wu, Research Associate and Lab Manager • Hyung Sik Kim, Ph.D., Visiting Professor from Sungkyunkwan University • Cong Wang, Ph.D. • Mallique Qader, Ph.D. • Kh Ahammad Uz Zaman, Ph.D. student • Lela DeVine, High School student
Biologically active compounds from natural sources: Natural products were and are still a rich source for drug discovery. One challenge is the rediscovery of known compounds. To avoid replication, Cao Lab is interested in studying the under-explored microorganisms in Hawaii. (i) The distribution and biologically active compounds of marine fungi have not been well studied compared with their counterparts in freshwater and terrestrial ecosystems. Few studies have addressed the occurrence of fungi in deep-sea sediments. Studies also showed that taxonomic and functional annotation of the transcriptome demonstrated that coral-associated fungi in Hawaii represent a diverse and metabolically active community, indicating that there is much to learn about fungi in corals. (ii) A total of 23,680 Hawaiian species have been documented, including 18,607 native Hawaiian species (9,151 indigenous species and 9,456 endemic species), and 5,073 human-introduced (non-native) species. Among the formally recognized species of native Hawaiian flowering plants, 88.9% are endemic to the Hawaiian islands. Research in the past ten years reveals that endophytic fungi are a rich source of biologically active secondary metabolites, but endophytic fungi are much underexplored. (iii) Bacteria, particularly actinimycetes, were traditionally the main source for drug discovery, especially for antibiotic. Many efforts have been focusing on discovering new drugs from old sources (for example, streptomyces), but it usually leads to the discovery of known natural products. More recently, efforts have been taken to reveal the cryptic natural products based on their unique genomic signatures. New technology enables scientists to study bacteria from new sources (for example, cyanobacteria, myxobacteria, uncultured bacteria, bacteria in lower animals, insects-associated bacteria, and bacteria from marine etc); and these adventures have resulted in the discovery of novel bioactive compounds with unique structural skeletons. Also, globally and locally remote, as well as physically and chemically diverse, Hawaiian aquatic habitats provide unique niches for the evolution of novel communities and microorganisms. Cao Lab is interested in finding new anticancer (& antibacterial and anti-fungal, etc.) natural products from marine and terrestrial fungi and bacteria collected in Hawaii, manipulating silent genes for the production of secondary metabolites, understanding how they are biosynthetically synthesized, and elucidating their mechanisms of action. Since the end of 2013, Cao Lab has published more than ten papers about anti-proliferative compounds, p53 reactivator, STAT3 & NF-kB inhibitors, and antibacterial & anti-fungal agents from Hawaiian fungi in “Org. Lett.”, “Sci. Rep.”, “Phytochemistry”, “Bioorg. Med. Chem. Lett.”, “Tetrahedron Lett.”, “Molecules”, and “Cancer Biol.” etc.
Herbal medicine: Herbal medicine has a long history, which is still used in many countries. Although herbal medicine is not part of the mainstream medical care in the USA, FDA has approved two botanic drugs, and will likely approve more. One challenge to study herbal medicine is the identification of biologically active molecules that account for the claimed therapeutic effects and mechanisms of action. Cao Lab is interested in studying traditional medicine used in the Asia-Pacific Region. In the past few years, Cao Lab has been studying some medicinal plants including Barleria lupulina and Morinda citrifolia. From these plants, Cao Lab has isolated many new compounds, identified a few previously unknown Nrf2 activators, and published some papers in “PLoS ONE”, “J. Ethnopharmacol.”, “J. Nat. Prod.”, “Tetrahedron Lett.”, “Bioorg. Med. Chem. Lett.”, and “J. Nat. Sci.” etc.
Ohashi M, Jamieson CS, Cai Y, Tan D, Kanayama D, Tang M, Anthony SM, Chari JV, Barber JS, Picazo E, Kakule TB, Cao S, Garg NK, Zhou J, Houk KN, Tang Y “Discovery of enzymatic Alder-ene reaction and origins of catalytic selectivity” Nature 2020, accepted on July 23rd 2020
Wang C, Wu X, Bai H, Zaman KAU, Hou S, Saito J, Wongwiwatthananukit S, Kim K-S, Cao S. “Lumazine Peptides, Aspochalasin, γ-Butyrolactone Derivatives and Cyclic Peptides with Antibacterial and NF-κB Inhibitory Activities from a Hawaiian Aspergillus flavipes” J. Nat. Prod. 2020, 83, accepted. doi: 10.1021/acs.jnatprod.0c00344.
Wang C, Tang S, Cao S. “Antimicrobial compounds from marine fungi” Phytochem. Rev. 2020, Accepted. DOI: 10.1007/s11101-020-09705-5
Wang C, Lu Y, Cao S. “Antimicrobial compounds from marine Actinomycetes” Arch. Pharm. Res. 2020, accepted
Park YJ, Kim KS, Park JH, Lee SH, Kim HR, Lee SH, Choi HB, Cao S, Kumar V, Kwak JH, HS. “Protective effects of dendropanoxide isolated from Dendropanax morbifera against cisplatin-induced acute kidney injury via the AMPK/mTOR signaling pathway” Food Chem. Toxicol. 2020, Accepted.
Wang F, Sarotti AM, Jiang G, Huguet-Tapia JC, Zheng SL, Wu X, Li C, Ding Y, Cao S. “Waikikiamides A-C: Complex Diketopiperazine Dimer and Diketopiperazine-Polyketide Hybrids from a Hawaiian Marine Fungal Strain Aspergillus sp. FM242”. Org. Lett. 2020, 22, 4408-4412.
Zaman KHAU, Hu Z, Wu X, Hou S, Saito J, Kondratyuk TP, Pezzuto JM, Cao S. “NF-κB Inhibitory and Antibacterial Helvolic and Fumagillin Derivatives from Aspergillus terreus” J. Nat. Prod. 2020, 83(3), 730-737.
Zaman KHAU, Hu Z, Wu X, Cao S. “Tryptoquivalines W and X, two new compounds from a Hawaiian fungal strain and their biological activities” Tetrahedron Lett. 2020, 61(14), Article 151730.
Sachan R, Kundu A, Dey P, Son JY, Kim KS, Lee DE, Kim HR, Park JH, Lee SH, Kim J-H , Cao S, Lee BM, Kwak JH, Kim HS.“Dendropanax morbifera Protects against Renal Fibrosis in Streptozotocin-Induced Diabetic Rats” Antioxidants, 2020, 9(1), pii:84. doi:10.3390/antiox9010084
Li C, Wang F, Wu X, Cao* S. “A new 24-homo-30-nor-cycloartane triterpenoid from a Hawaiian endophytic fungal strain” Tetrahedron Lett. 2020, 61(7), Article 151508.
Cai Y, Xu J, Chen M, Wang D, Yang Y, Manavalan A, Wu X, Liu Y, Cao* S. “Compound Analysis of Jing Liqueur and nrf2 Activation by Jing Liqueur—One of the Most Popular Beverages in China.” Beverages 2020, 6(1), 1.
Cai Y, Wu Z, Zheng X-Q, Wang C, Wang J-R, Zhang X-X, Qiu G, Zhu K, Cao S, Yu J “Spiroalanpyrroids A and B, sesquiterpene alkaloids with a unique spiro-eudesmanolide–pyrrolizidine skeleton from Inula helenium” Org. Chem. Front. 2020, 7, 303-309.
Wang F, Hu Z, Li C, Wu X, Cao* S. “Circumdatin M, a new benzodiazepine alkaloid with a unique pyrimidone-4-pyrone moiety from a Hawaiian marine fungus Aspergillus sp. FM242.” Tetrahedron Lett.2019, 60, 1724-1726.
Wang Q, Hu Z, Luo X, Liu J, Li* G, Cao* S, Liu* Q. “Clavukoellians A-G, Highly Rearranged Nardosinane Sesquiterpenoids with Anti-angiogenic Activity from Clavularia koellikeri” J. Nat. Prod.2019,82(5), 1331-1337.
Li C, Sarotti AM, Wu X, Yang B, Turkson J, Chen Y, Liu Q, Cao* S. “An Unusual Benzoisoquinoline-9-one Derivative and Other Related Compounds with Antiproliferative Activity from Hawaiian Endophytic Fungus Peyronellaea sp. FT431.” Molecules. 2019 Jan 7;24(1). pii: E196. doi: 10.3390/molecules24010196.
Wang Q, Hu Z, Li X, Wang A, Wu H, Liu J, Cao* S, Liu* Q. “Salviachinensines A-F, New Anti-leukemic Phenolic Acids from Chinese Herbal Medicine Salvia chinensis Benth” J. Nat. Prod.2018,81(11), 2531-2538. doi: 10.1021/acs.jnatprod.8b00638.
Li C, Hu Z, Liu Q, Wu X, Cao* S. “Two new tricycloalternarenes from Hawaiian endophytic fungus Didymella sp. FT433” Tetrahedron Lett.2018, 59(36), 3381-3383.
Cai* Y-S, Sarotti AM, Zhou T-L, Huang R, Qiu Q, Tian C, Miao Z-H, Mándi A, Kurtán T, Cao* S, Yang* S-P. “Flabellipparicine, a Flabelliformide-Apparicine-Type Bisindole Alkaloids from Tabernaemontana divaricata.” J. Nat. Prod.2018,81(9), 1976-1983.
Nilubol N, Yuan Z-Q, Paciott GP, Tamarkin L, Sanchez C, Gaskins K, Freedman EM, Cao S, Zhao J, Kingston DGI, Libutti SK, Kebebew E. “A Novel Dual-Action Targeted Nanomedicine Effective in Mouse Models of Endocrine Cancers” J Natl Cancer Inst. 2018, 110(9), 1019-1029. doi: 10.1093/jnci/djy003
Li C, Sarotti AM, Wesley Y, Cao S. “Two new polyketides from Hawaiian endophytic fungus Pestalotiopsis sp. FT172” Tetrahedron Lett.2018, 58, 42-45.
Cai Y-S, Sarotti AM, Gündisch D,. Kondratyuk TP, Pezzuto JM, Turkson J, Cao*, S. “Heliotropiumides A and B, new phenolamides with N-carbamoyl putrescine moiety from Heliotropium foertherianum collected in Hawaii and their biological activities” Bioorg. Med. Chem. Lett.2017, 27, 4630-4634.
Li C-S, Sarotti AM, Huang P, Dang UT, Hurdle J, Kondratyuk TP, Pezzuto JM, Turkson J, Cao, S. “NF-κB inhibitors, unique γ-pyranol-γ-lactams with sulfide and sulfoxide moieties from Hawaiian plant Lycopodiella cernua derived fungus Paraphaeosphaeria neglecta FT462” Sci. Rep.2017, 7(1):10424.
Li C, Sarotti AM, Yang B, Turkson J, Cao S. “A New N-methoxypyridone from the Co-Cultivation of Hawaiian Endophytic Fungi Camporesia sambuci FT1061 and Epicoccum sorghinum FT1062” Molecules2017, 22(7), 1166.
Li C, Sarotti AM, Turkson J, Cao S. “Verbenanone, an octahydro-5H-chromen-5-one from a Hawaiian-Plant Associated Fungus FT431” Tetrahedron Lett., 2017, 58, 2290–2293.
Li C, Yang B, Turkson J, Cao* S. Anti-proliferative ambuic acid derivatives from Hawaiian endophytic fungus Pestalotiopsis sp. FT172 Phytochem.2017, 140, 77–82.
Wyche TP, Ruzzini AC, Beemelmanns C, Kim KH, Klassen JL, Cao S, Poulsen M, Bugni TS, Currie CR, Clardy J. “Linear peptides are the major products of a biosynthetic pathway that encodes for cyclic depsipeptides” Org Lett.2017, 19(7), 1772–1775.
Huang P, Li C, Sarotti AM, Turkson J, Cao S. “Sphaerialactonam, a γ-lactam-isochromanone from the Hawaiian endophytic fungus Paraphaeosphaeria sp. FT462” Tetrahedron Lett., 2017, 58, 1330–1333.
Beemelmanns C, Ramadhar TR, Kim KH, Klassen JL, Cao S, Wyche TP, Hou Y, Poulsen M, Bugni TS, Currie CR, Clardy J. “Macrotermycins A-D, Glycosylated Macrolactams from a Termite-Associated Amycolatopsis sp. M39.” Org Lett.2017, 19(5), 1000–1003.
Paciotti GF, Zhao J, Cao S, Brodie PJ, Tamarkin L, Huhta M, Myer LD, Friedman J, Kingston* DGI. “Synthesis and Evaluation of Paclitaxel-Loaded Gold Nanoparticles for Tumor-Targeted Drug Delivery” Bioconj. Chem.2016, 27 (11), 2646–2657
Senger DR, Cao S. “Diabetic Wound Healing and Activation of Nrf2 by Herbal Medicine” J. Nat. Sci. 2016, 2(11):e247
Briggs KJ, Koivunen P, Cao S, Backus KM, Olenchock BA, Patel H, Zhang Q, Signoretti S, Gerfen GJ, Richardson AL, Witkiewicz AK, Cravatt BF, Clardy, Kaelin* WG. Jr. “Paracrine Induction of HIF by Glutamate in Breast Cancer: EglN1 Senses Cysteine” Cell2016, 166(1), 126-139.
Senger DR, Hoang MV, Kim KH, Li C, Cao* S. “Anti-inflammatory activity of Barleria lupulina: Identification of active compounds that activate the Nrf2 cell defense pathway, organize cortical actin, reduce stress fibers, and improve cell junctions in microvascular endothelial cells” J. Ethnopharmacology 2016, 193, 397-407.
Fei-Zhang DJ, Li C, Cao* S. “Hawaii Natural Compounds are Promising to Reduce Ovarian Cancer Deaths” Cancer Biology and Therapy2016, May 4:1-4.
Li C, Ren G, Yang B, Miklossy G, Turkson J, Fei P, Ding Y, Walker LA, Cao* S. “Meroterpenoids with anti-proliferative activi-ty from a Hawaiian-Plant Associated Fungus Peyronellaea coffeae-arabicae FT238” Org. Lett.2016, 18(10), 2335-2338.
Lee SR, Clardy J, Senger DR, Cao* S, Kim* KH. “Phytochemical constituents from the aerial part of Barleria lupulina” Revista Brasileira de Farmacognosia 2016, 26, 281-284.
Lee SR, Beemelmanns C, Tsuma LM, Clardy J, Cao* S, Kim* KH. “A New Diketopiperazine, Cyclo(D-trans-Hyp-L-Leu) from a Kenyan Bacteria Bacillus licheniformis LB 8CT” Nat. Prod. Comm. 2016, 11(4), 461-463.
Lee S, Clardy J, Cao* S, Kim* KH. “Diketopiperazines from a Costa Rican funus Colpoma sp. CR1465A” Bioorg. Med. Chem. Lett. 2016, 26, 2438-2441.
Li C, Ding Y, Yang B, Yin H-Q, Turkson J, Cao* S. “Antiproliferative sesquiterpenes from Hawaiian endophytic fungus Chaetoconis sp. FT087” Phytochem.2016, 126, 41-46.
Senger DR, Li D, Jaminet SC, Cao S. “Activation of the Nrf2 cell defense pathway by ancient foods: Disease prevention by important molecules and microbes lost from the modern Western diet” PLoS ONE2016, e0148042; DOI:10.1371.
Wang Y, Qi S, Zhan Y, Zhang N, Wu A, Gui F, Guo K, Yang Y, Cao S, Hu Z, Zheng Z, Song S, Xu Q, Shen Y, Deng X. “Aspertetranones A-D, Meroterpenoids from the Marine Algal-associated Fungus Aspergillus sp.” J. Nat. Prod. 2015, 78(10), 2405-2410.
Cheng KCC,+ Cao S,+ Raveh A,+ MacArthur R, Dranchak P, Chipala G, Okoneski M, Guha R, Eastman R, Yuan J, SchultzP, Su X-Z, Tamayo-Castillo G, Matainaho T, Clardy J, Sherman D,* Inglese J.* “Actinoramide A stereoisomer identified as potent anti-malarial from titration-based screening of marine natural product extracts” J. Nat. Prod. 2015, 78(10), 2411-2422. (+ Co-first author/Equal contribution)
Hiraki M,+ Hwang S-Y,+ Cao S,+ Ramadhar TR, T. Byun S, Yoon KW, K. Chu K, Gurkar AU, A. Vihren Kolev V, Zhang J, Namba T, Murphy ME, Aaronson SA, Newman DJ, Mandinova A, Clardy J,* Lee SW.* “Small molecule reactivation of mutant p53 to wt-like p53 through the p53-Hsp40 regulatory axis” Chemistry & Biology2015, 22(9), 1206-1216. (+Co-first author/Equal contribution)
Li C, Ding Y, Yang B, Miklossy G, Yin H-Q, Walker LA, Turkson J, Cao S*. “A Novel Metabolite with a Unique 4-pyranone–γ-lactam–1,4-thiazine moiety from a Hawaiian-Plant Associated Fungus (FT462)” Org. Lett.2015, 17(14), 3556-3559.
Kim KH, Beemelmanns C, Clardy J, Cao* S. “A new antimicrobial octaketide and cytotoxic phenylethanoid glycosides from Pogostemon cablin (Blanco) Benth” Bioorg. Med. Chem. Lett.2015, 25, 2834-2836.
Kim KH, Clardy J, Senger DR, Cao* S. “Chakyunglupulins A and B, two novel 4,8,8-trimethylcyclooct-2-enone derivatives from Barleria lupulina”Tetrahedron Lett. 2015, 56, 2732-2734.
Li C, Yang B, Fenstemacher R, Turkson J, Cao S.* “Lycopodiellactone, an unusual δ-lactone-isochromanone from a Hawaiian plant-associated fungus Paraphaeosphaeria neglecta FT462” Tetrahedron Lett.2015, 56, 1724-1727.
Kim KH, Park YJ, Chung KH, Yip MLR, Clardy J, Senger DR, Cao S.* “Iridoid Glycosides from Barleria lupulina”J. Nat. Prod.2015, 78, 320-324.
Wei S, Kozono S, Kats L, Nechama M, Li W, Guarnerio J, Luo M, You M-H, Yao Y, Kondo A, Hu H, Bozkurt G, Moerke NJ, Cao S, Reschke M, Chen C-H, Rego EM, LoCoco F, Cantley L, Lee TH, Wu H, Zhang Y, Pandolfi PP, Zhou ZZ, Z. Lu K-P.* “Active Pin1 is a key target of all-trans retinoic acid in acute promyelocytic leukemia and breast cancer” Nature Medicine2015, 21(5), 457-466.