Co-reporter:Vedanjali Gogineni, Raymond F. Schinazi, and Mark T. Hamann
Chemical Reviews 2015 Volume 115(Issue 18) pp:9655
Publication Date(Web):August 28, 2015
DOI:10.1021/cr4006318
Co-reporter:In Hyun Hwang, Joonseok Oh, Wei Zhou, Seoyoung Park, Joo-Hyun Kim, Amar G. Chittiboyina, Daneel Ferreira, Gyu Yong Song, Sangtaek Oh, MinKyun Na, and Mark T. Hamann
Journal of Natural Products 2015 Volume 78(Issue 3) pp:453-461
Publication Date(Web):January 15, 2015
DOI:10.1021/np500843m
Colorectal cancer has emerged as a major cause of death in Western countries. Down-regulation of β-catenin expression has been considered a promising approach for cytotoxic drug formulation. Eight 4,9-friedodrimane-type sesquiterpenoids (1–8) were acquired using the oxidative potential of Verongula rigida on bioactive metabolites from two Smenospongia sponges. Compounds 3 and 4 contain a 2,2-dimethylbenzo[d]oxazol-6(2H)-one moiety as their substituted heterocyclic residues, which is unprecedented in such types of meroterpenoids. Gauge-invariant atomic orbital NMR chemical shift calculations were employed to investigate stereochemical details with support of the application of advanced statistics such as CP3 and DP4. Compounds 2 and 8 and the mixture of 3 and 4 suppressed β-catenin response transcription (CRT) via degrading β-catenin and exhibited cytotoxic activity on colon cancer cells, implying that their anti-CRT potential is, at least in part, one of their underlying antineoplastic mechanisms.
Co-reporter:Dr. Ama L. Waters;Dr. Joonseok Oh; Allen R. Place; Mark T. Hamann
Angewandte Chemie International Edition 2015 Volume 54( Issue 52) pp:15705-15710
Publication Date(Web):
DOI:10.1002/anie.201507418
Abstract
After publication of karlotoxin 2 (KmTx2; 1), the harmful algal bloom dinoflagellate Karlodinium sp. was collected and scrutinized to identify additional biologically active complex polyketides. The structure of 1 was validated and revised at C49 using computational NMR tools including J-based configurational analysis and chemical-shift calculations. The characterization of two new compounds [KmTx8 (2) and KmTx9 (3)] was achieved through overlaid 2D HSQC NMR techniques, while the relative configurations were determined by comparison to 1 and computational chemical-shift calculations. The detailed evaluation of 2 using the NCI-60 cell lines, NMR binding studies, and an assessment of the literature supports a mode of action (MoA) for targeting cancer-cell membranes, especially of cytostatic tumors. This MoA is uniquely different from that of current agents employed in the control of cancers for which 2 shows sensitivity.
Co-reporter:Dr. Ama L. Waters;Dr. Joonseok Oh; Allen R. Place; Mark T. Hamann
Angewandte Chemie 2015 Volume 127( Issue 52) pp:15931-15936
Publication Date(Web):
DOI:10.1002/ange.201507418
Abstract
After publication of karlotoxin 2 (KmTx2; 1), the harmful algal bloom dinoflagellate Karlodinium sp. was collected and scrutinized to identify additional biologically active complex polyketides. The structure of 1 was validated and revised at C49 using computational NMR tools including J-based configurational analysis and chemical-shift calculations. The characterization of two new compounds [KmTx8 (2) and KmTx9 (3)] was achieved through overlaid 2D HSQC NMR techniques, while the relative configurations were determined by comparison to 1 and computational chemical-shift calculations. The detailed evaluation of 2 using the NCI-60 cell lines, NMR binding studies, and an assessment of the literature supports a mode of action (MoA) for targeting cancer-cell membranes, especially of cytostatic tumors. This MoA is uniquely different from that of current agents employed in the control of cancers for which 2 shows sensitivity.
Co-reporter:Xia Yan, James Sims, Bin Wang, Mark T. Hamann
Biochemical Systematics and Ecology 2014 Volume 55() pp:292-295
Publication Date(Web):August 2014
DOI:10.1016/j.bse.2014.03.015
•We identified Streptomyces sp. ISP2-49E from marine sediment of the Gulf of Mexico.•We isolated a biologically active rhamnolipid from the media of a ISP2-49E culture.•This is the first documented production of a rhamnolipid from Streptomyces spp.•Rhamnolipids as an adaptation for hydrocarbon contaminated environments is proposed.Marine derived actinomycetes were isolated from sediment samples of Galveston Bay, Texas and screened for production of bioactive metabolites. Streptomyces sp. ISP2-49E, identified by 16s rDNA, produced a previously described Rha-Rha-C10-C10 rhamnolipid; however, this is the first report of a rhamnolipid produced by a Streptomyces sp. This organism was isolated from hydrocarbon contaminated sediment and further supports the trend of rhamnolipid production as a potential adaptation to this environment.
Co-reporter:John J. Bowling, James B. Anderson, Kevin L. Armbrust, Mark T. Hamann
Fuel 2014 Volume 117(Part A) pp:5-7
Publication Date(Web):30 January 2014
DOI:10.1016/j.fuel.2013.08.058
Oil production from single cells has been in development since the 1980s primarily for the pharmaceutical and neutraceutical industries, but the technology for using microorganisms to convert plant cellular material directly into oil is still undeveloped. The unusual amount of oil extracted from the imported fire ant (Solenopsis sp.) may be an indication of the presence of oleaginous microorganisms or enzymes supporting the digestion of raw sugars. Yield of the ant oil is 16% dry weight and contains most of the fatty acids also found in other biomass resources. Heat of combustion of the ant oil was 133,000 BTU/gal, an amount within the range of reported values for vegetable oil and biodiesel. This investigation also explores the potential source of the oil through stable isotope labeling and offers a unique perspective of a potentially new source of microorganisms or enzymes useful for reducing the cost of producing an alternative fuel.
Co-reporter:Yike Zou and Mark T. Hamann
Organic Letters 2013 Volume 15(Issue 7) pp:1516-1519
Publication Date(Web):March 8, 2013
DOI:10.1021/ol400294v
A new pyrroloiminoquinone alkaloid, named atkamine, with an unusual scaffold was discovered from a cold, deep water Alaskan sponge Latrunculia sp. collected from the Aleutian Islands. Olefin metathesis was utilized to determine the location of the double bond in the hydrocarbon chain. The absolute configuration was determined by using computational approaches combing with the ECD (electronic circular dichroism) spectroscopy.
Co-reporter:Mohamed A. Albadry ; Khaled M. Elokely ; Bin Wang ; John J. Bowling ; Mohamed F. Abdelwahab ; Mohamed H. Hossein ; Robert J. Doerksen ;Mark T. Hamann
Journal of Natural Products 2013 Volume 76(Issue 2) pp:178-185
Publication Date(Web):January 30, 2013
DOI:10.1021/np3006088
Assignment of the absolute configuration of cyclic peptides frequently yields challenges, leaving one or more stereogenic centers unassigned due to small quantities of sample and the limited utility of Marfey’s or other methods for assigning amino or hydroxy acids. Here, we report isolation of kahalalide Y (1) from Bryopsis pennata for the first time; in addition, the application of a combination of molecular modeling and NOE distance constraint calculations was utilized to determine the conformation of 1 and the absolute configuration of the final stereogenic center of 1. Using the Schrödinger suite, the structure of 1 was sketched in Maestro and minimized using the OPLS2005 force field in Macromodel. A conformational search was performed separately for structures having an R or S configuration at C-3 of the beta-hydroxy fatty acid subunit that completes the cyclic scaffold of 1, after which multiple minimizations for all generated conformers were carried out. The lowest energy conformers of R and S stereoisomers were then subjected to B3LYP geometry optimizations including solvent effects. The S stereoisomer was shown to be in excellent agreement with the NOE-derived distance constraints and hydrogen-bonding stability studies.
Co-reporter:Takashi Tomioka, Yusuke Takahashi, Toshihide Maejima, Yuki Yabe, Hiroki Iwata, Mark T. Hamann
Tetrahedron Letters 2013 Volume 54(Issue 48) pp:6584-6586
Publication Date(Web):27 November 2013
DOI:10.1016/j.tetlet.2013.09.104
Starting from natural d-mannose, a C(42–63) B-ring tetrahydropyran fragment in karlotoxin 2 has been prepared via a common THP intermediate in a concise manner. E-Selective Julia–Kocienski olefination efficiently assembled a C(51–63) chlorodiene subunit and a C(42–50) tetrahydropyran segment.
Co-reporter:In Hyun Hwang, Joonseok Oh, Anna Kochanowska-Karamyan, Robert J. Doerksen, MinKyun Na, Mark T. Hamann
Tetrahedron Letters 2013 Volume 54(Issue 29) pp:3872-3876
Publication Date(Web):17 July 2013
DOI:10.1016/j.tetlet.2013.05.032
A novel phenyl alkene (1) was isolated from a mixture of three Florida sponges, Smenospongia aurea, Smenospongia cerebriformis, and Verongula rigida. Unlike terpenoids or amino acid derivatives, which are commonly known classes of secondary metabolites from these genera, the chemical structure of 1 showed an unprecedented linear phenyl alkene skeleton. Through comprehensive analyses of NMR and MS data, the gross structure of 1 was determined to be (E)-10-benzyl-5,7-dimethylundeca-1,5,10-trien-4-ol. The absolute configuration at C-4 was established as R by a modified Mosher’s method. Based on the relative configuration between C-4 and C-7, the absolute configuration at C-7 was assigned as S. Compound 1 showed in vitro cytotoxic activity against HL-60 human leukemia cancer cells with an IC50 value of 8.1 μM. Molecular docking study suggests that the structure of compound 1 matches the pharmacophore of eribulin required to display cytotoxic activity through the inhibition of microtubule activity.
Co-reporter:Tony Whitaker;MinKyun Na;Raymond F. Schinazi;David J. Newman;Mohamed Ali Ibrahim;Tami R. McBrayer;Joonseok Oh;Robert J. Doerksen;Louis G. Zachos;Mark T. Hamann
PNAS 2013 Volume 110 (Issue 42 ) pp:16832-16837
Publication Date(Web):2013-10-15
DOI:10.1073/pnas.1311528110
One in five of the world’s plant species is threatened with extinction according to the 2010 first global analysis of extinction
risk. Tilman et al. predicted a massive ecological change to terrestrial plants within the next 50–100 y, accompanied by an
increase in the number of global plant species facing extinction [Tilman D, et al. (2001) Proc Natl Acad Sci USA 98(10):5433–5440]. Most of the drug-producing plant families contain endangered species never previously studied for their
utility to human health, which strongly validates the need to prioritize protection and assessment of these fragile and endangered
groups [Zhu F, et al. (2011) Proc Natl Acad Sci USA 108(31):12943–12948]. With little prior attention given to endangered and rare plant species, this report provides strong
justification for conservation of the rare plant Diplostephium rhododendroides Hieron., as well as other potential drug-producing endangered species in this and other groups.
Co-reporter:Amir E. Wahba, Yann Fromentin, Yike Zou, Mark T. Hamann
Tetrahedron Letters 2012 Volume 53(Issue 47) pp:6329-6331
Publication Date(Web):21 November 2012
DOI:10.1016/j.tetlet.2012.08.140
A new manzamine-related alkaloid with unprecedented δ-lactone and ε-lactam rings called acantholactone (2), was isolated from the Indonesian sponge Acanthostrongylophora sp. The relative configuration of the two new ring systems was established through detailed analysis of NOESY correlations combined with molecular modeling studies. The absolute configuration of 2 was determined as 12S, 24R, 25R, 26R by comparing the computed electronic circular dichroism (ECD) spectra with experimental values.
Co-reporter:Joonseok Oh, John J. Bowling, John F. Carroll, Betul Demirci, K. Hüsnü Can Başer, Theodor D. Leininger, Ulrich R. Bernier, Mark T. Hamann
Phytochemistry 2012 80() pp: 28-36
Publication Date(Web):
DOI:10.1016/j.phytochem.2012.05.001
Co-reporter:Amir E. Wahba and Mark T. Hamann
The Journal of Organic Chemistry 2012 Volume 77(Issue 10) pp:4578-4585
Publication Date(Web):April 9, 2012
DOI:10.1021/jo300303d
A simple, mild, cost-effective, and green approach for the reductive mono-N-alkylation of nitroarenes has been developed. HOAc/Zn are utilized as the reducing system together with a carbonyl compound as an alkyl source in methanol. Excellent yields were obtained with stoichiometric control of mono- over dialkylated products. Application to five complex natural products demonstrated the practical utility of the method.
Co-reporter:Jiangtao Gao and Mark T. Hamann
Chemical Reviews 2011 Volume 111(Issue 5) pp:3208
Publication Date(Web):April 11, 2011
DOI:10.1021/cr100187n
Co-reporter:Abbas Gholipour Shilabin, Mark T. Hamann
Bioorganic & Medicinal Chemistry 2011 Volume 19(Issue 22) pp:6628-6632
Publication Date(Web):15 November 2011
DOI:10.1016/j.bmc.2011.06.050
Kahalalide F (KF) and the regioisomer isoKF are novel anticancer drugs of marine origin and currently under clinical investigation. Here we report the synthesis of two new KF analogs with significant in vitro and in vivo antifungal and antitumor activities. The primary amine hydrogen of ornithine in KF has been replaced with 4-fluoro-3-methylbenzyl and morpholin-4-yl-benzyl via reductive N-alkylation. The TGI of these analogs using the NCI-60 cell line screening revealed promising results when compared to paclitaxel. The result of in vivo hollow fiber and animal toxicity assays are presented.
Co-reporter:Anna J. Kochanowska-Karamyan and Mark T. Hamann
Chemical Reviews 2010 Volume 110(Issue 8) pp:4489
Publication Date(Web):April 9, 2010
DOI:10.1021/cr900211p
Co-reporter:Jiangnan Peng ; Allen R. Place ; Wesley Yoshida ; Clemens Anklin ;Mark T. Hamann
Journal of the American Chemical Society 2010 Volume 132(Issue 10) pp:3277-3279
Publication Date(Web):February 15, 2010
DOI:10.1021/ja9091853
In an attempt to determine the cause of repeated fish kills in an estuarine aquaculture facility in Maryland, a toxin with hemolytic, cytotoxic, and ichthyotoxic properties, designated as karlotoxin-2 (KmTx2), was isolated from Karlodinium veneficum. The structure of KmTx2 was elucidated by means of detailed ID and 2D NMR spectra, including 2D INADEQUATE. The relative and absolute configurations of KmTx2 were determined using J-based configuration analysis and comparison of its degradation products with synthetic controls.
Co-reporter:Jiangnan Peng ; Sucheta Kudrimoti ; Sivaprakasam Prasanna ; Srinivas Odde ; Robert J. Doerksen ; Hari K Pennaka ; Yeun-Mun Choo ; Karumanchi V. Rao ; Babu L. Tekwani ; Vamsi Madgula ; Shabana I. Khan ; Bin Wang ; Alejandro M. S. Mayer ; Melissa R. Jacob ; Lan Chun Tu ; Jürg Gertsch ▽;Mark T. Hamann
Journal of Medicinal Chemistry 2010 Volume 53(Issue 1) pp:61-76
Publication Date(Web):December 17, 2009
DOI:10.1021/jm900672t
Structure−activity relationship studies were carried out by chemical modification of manzamine A (1), 8-hydroxymanzamine A (2), manzamine F (14), and ircinal isolated from the sponge Acanthostrongylophora. The derived analogues were evaluated for antimalarial, antimicrobial, and antineuroinflammatory activities. Several modified products exhibited potent and improved in vitro antineuroinflammatory, antimicrobial, and antimalarial activity. 1 showed improved activity against malaria compared to chloroquine in both multi- and single-dose in vivo experiments. The significant antimalarial potential was revealed by a 100% cure rate of malaria in mice with one administration of 100 mg/kg of 1. The potent antineuroinflammatory activity of the manzamines will provide great benefit for the prevention and treatment of cerebral infections (e.g., Cryptococcus and Plasmodium). In addition, 1 was shown to permeate across the blood−brain barrier (BBB) in an in vitro model using a MDR-MDCK monolayer. Docking studies support that 2 binds to the ATP-noncompetitive pocket of glycogen synthesis kinase-3β (GSK-3β), which is a putative target of manzamines. On the basis of the results presented here, it will be possible to initiate rational drug design efforts around this natural product scaffold for the treatment of several different diseases.
Co-reporter:MinKyun Na, Yuanqing Ding, Bin Wang, Babu L. Tekwani, Raymond F. Schinazi, Scott Franzblau, Michelle Kelly, Robert Stone, Xing-Cong Li, Daneel Ferreira and Mark T. Hamann
Journal of Natural Products 2010 Volume 73(Issue 3) pp:383-387
Publication Date(Web):September 23, 2009
DOI:10.1021/np900281r
Bioassay- and LC-MS-guided fractionation of a methanol extract from a new deep-water Alaskan sponge species of the genus Latrunculia resulted in the isolation of two new brominated pyrroloiminoquinones, dihydrodiscorhabdin B (1) and discorhabdin Y (2), along with six known pyrroloiminoquinone alkaloids, discorhabdins A (3), C (4), E (5), and L (6), dihydrodiscorhabdin C (7), and the benzene derivative 8. Compounds 3, 4, and 7 exhibited anti-HCV activity, antimalarial activity, and selective antimicrobial activity. Although compounds 3 and 7 displayed potent and selective in vitro antiprotozoal activity, Plasmodium berghei-infected mice did not respond to these metabolites due to their toxicity in vivo.
Co-reporter:Yang-Qing He, Zhan-Ying Ma, Qian Yang, Bao-Zhong Du, Zhan-Xin Jing, Bing-Hua Yao, Mark T. Hamann
Biochemical Systematics and Ecology 2010 Volume 38(Issue 4) pp:554-556
Publication Date(Web):August 2010
DOI:10.1016/j.bse.2010.06.004
Ten compounds (1–10) including two C20-diterpenoid alkaloids, five C19-diterpenoid alkaloids, one triterpenoid and two flavonoids were isolated from the whole plant material of Delphinium albocoeruleum Maxim for the first time. The chemotaxonomic significance of these compounds was summarized.
Co-reporter:John J. Bowling;Rabab Mohammed;Jeffrey A. Diers;Mark T. Hamann
Chemoecology 2010 Volume 20( Issue 3) pp:207-213
Publication Date(Web):2010 September
DOI:10.1007/s00049-010-0049-z
Marine sponges of the Genus Plakortis are typically unfouled; they can have a distinctive pleasant smell and an oily surface. A significant quantity of fragrant oil was obtained from a Jamaican Plakortis sp. by cryo-trap. The oil was determined to be exclusively 2-decanone. The antifouling character of the oil was evaluated by its effects on surface attachment of a gram negative bacterial model using confocal fluorescence microscopy as well as its effects on the attachment of Dreissena polymorpha (zebra mussel). The ketone dramatically inhibited attachment of the bacteria and zebra mussels. The results suggest that the oil impacts establishment of related epifauna on the Plakortis sponge in nature. Although the aliphatic ketone alone is not a potential commercial alternative for antifouling coatings, incorporating the functionality into coating design should be considered in future studies.
Co-reporter:Mohamed A. Ibrahim, Arsala A. Mansoor, Amanda Gross, M. Khalid Ashfaq, Melissa Jacob, Shabana I. Khan and Mark T. Hamann
Journal of Natural Products 2009 Volume 72(Issue 12) pp:2141-2144
Publication Date(Web):November 11, 2009
DOI:10.1021/np900499q
One known and three new potent, selective, and nontoxic anti-MRSA metabolites, kaempferol 3-O-α-l-(2′′,3′′-di-E-p-coumaroyl)rhamnoside (1) (IC50 2.0 μg/mL), kaempferol 3-O-α-l-(2′′-E-p-coumaroyl-3′′-Z-p-coumaroyl)rhamnoside (2) (IC50 0.8 μg/mL), kaempferol 3-O-α-l-(2′′-Z-p-coumaroyl-3′′-E-p-coumaroyl)rhamnoside (3) (IC50 0.7 μg/mL), and kaempferol 3-O-α-l-(2′′,3′′-di-Z-p-coumaroyl)rhamnoside (4) (IC50 0.4 μg/mL), were isolated from the leaves of the common American sycamore, Platanus occidentalis. Compounds 2−4 are new. Due to the unusual selectivity, potency, and safety of the pure compounds and the semipure glycoside mixture against MRSA, it is clear that this represents a viable class of inhibitors to prevent growth of MRSA on surfaces and systemically.
Co-reporter:Jiangtao Gao, Catherina Caballero-George, Bin Wang, Karumanchi V. Rao, Abbas Gholipour Shilabin and Mark T. Hamann
Journal of Natural Products 2009 Volume 72(Issue 12) pp:2172-2176
Publication Date(Web):November 16, 2009
DOI:10.1021/np900287e
Two new cyclic depsipeptides, 5-OHKF (1) and norKA (2), together with the known congeners kahalalide F (3) and isokahalalide F ((4S)- methylhexanoic kahalalide F) (4) were isolated from the green alga Bryopsis pennata. The structures of the new compounds were established on the basis of extensive 1D and 2D NMR spectroscopic analysis and mass spectrometric (ESIMS) data. The absolute configuration of each amino acid of 5-OHKF (1) and norKA (2) was determined by chemical degradation and Marfey’s analysis. The biological activities of these two compounds are also reported.
Co-reporter:Amir E. Wahba, Jiangnan Peng, Sucheta Kudrimoti, Babu L. Tekwani, Mark T. Hamann
Bioorganic & Medicinal Chemistry 2009 Volume 17(Issue 22) pp:7775-7782
Publication Date(Web):15 November 2009
DOI:10.1016/j.bmc.2009.09.026
Twenty manzamine amides were synthesized and evaluated for in vitro antimalarial and antimicrobial activities. The amides of manzamine A (1) showed significantly reduced cytotoxicity against Vero cells, although were less active than 1. The structure–activity analysis showed that linear, short alkyl groups adjacent to the amide carbonyl at position 8 are favored for antimalarial activity, while bulky and cyclic groups at position 6 provided the most active amides. Most of the amides showed potent activity against Mycobacterium intracellulare. The antimicrobial activity profile for position 8 series was similar to that for antimalarial activity profile, in which linear, slightly short alkyl groups adjacent to the amide carbonyl showed improved activity. Two amides 14 and 21, which showed potent antimalarial activity in vitro against Plasmodium falciparum were further evaluated in vivo in Plasmodium berghei infected mice. Oral administration of 14 and 21 at the dose of 30 mg/kg (once daily for three days) caused parasitemia suppression of 24% and 62%, respectively, with no apparent toxicity.
Co-reporter:Sucheta Kudrimoti, Safwat A. Ahmed, Pankaj R. Daga, Amir E. Wahba, Sherief I. Khalifa, Robert J. Doerksen, Mark T. Hamann
Bioorganic & Medicinal Chemistry 2009 Volume 17(Issue 21) pp:7517-7522
Publication Date(Web):1 November 2009
DOI:10.1016/j.bmc.2009.09.012
Latrunculins are unique macrolides containing a thiazolidinone moiety. Latrunculins A, B and T and 16-epi-latrunculin B were isolated from the Red Sea sponge Negombata magnifica. N-Alkylated, O-methylated analogs of latrunculin B were synthesized and biological evaluation was performed for antifungal and antiprotozoal activity. The natural latrunculins showed significant bioactivity, while the semisynthetic analogs did not. Docking studies of these analogs into the X-ray crystal structure of G-actin showed that, in comparison with latrunculins A and B, N-alkylated latrunculins did not dock satisfactorily. This suggests that the analogs do not fit well into the active site of G-actin due to steric clashes and provides an explanation for the absence of bioactivity.
Co-reporter:Amir E. Wahba, Jiangnan Peng, Mark T. Hamann
Tetrahedron Letters 2009 50(27) pp: 3901-3904
Publication Date(Web):
DOI:10.1016/j.tetlet.2009.04.061
Co-reporter:Abbas Gholipour Shilabin, Noer Kasanah, Babu L. Tekwani and Mark T. Hamann
Journal of Natural Products 2008 Volume 71(Issue 7) pp:1218-1221
Publication Date(Web):July 4, 2008
DOI:10.1021/np800163u
The manzamines represent a class of marine natural products that show considerable promise in the control of malaria but generate GI distress in rodents when administered orally in high doses. In an effort to generate manzamine prodrugs with improved antimalarial activity and reduced GI toxicity, we prepared acetylated 8-hydroxymanzamine A analogues including 8-acetoxymanzamine A (3) and 8,12-diacetoxymanzamine A (4), and 8-methoxymanzamine A (5) beginning with 8-hydroxymanzamine A (2). The semisynthetic analogues were assayed for antimalarial and antimicrobial activities, cytotoxicity, and biological and chemical stability. Due to gradual hydrolysis of the ester group, application of monoacetate 3 as an antimalarial prodrug was investigated. The in vitro and in vivo bioassays show that acetylated analogues exhibit significant antimalarial activity (IC50(3) 9.6−30 ng/mL), which are comparable to the parent molecule; however the monoaceate 3 was shown to actually produce higher toxicity at 30 mg/kg when administered orally.
Co-reporter:Karumanchi V. Rao, MinKyun Na, Jennifer C. Cook, Jiangnan Peng, Rae Matsumoto and Mark T. Hamann
Journal of Natural Products 2008 Volume 71(Issue 5) pp:772-778
Publication Date(Web):April 12, 2008
DOI:10.1021/np070508g
Four new kahalalides, V (1), W (2), X (3), and Y (4), as well as six previously characterized kahalalides have been isolated from a two-year collection of the sacoglossan mollusk Elysia rufescens. Curiously, kahalalide B, previously isolated in high yield from E. rufescens, was found to be essentially absent from these collections despite identical collection sites and times with previous collections. In addition, kahalalide K, which to date has only been reported from Bryopsis sp., was found in this collection of E. rufescens, suggesting that the production of these metabolites could potentially be from a microbial association with the mollusk and algae, and this relationship is continuously evolving in response to changes in the environment and predation. The structures of new peptides have been established on the basis of extensive 1D and 2D NMR spectroscopic data analysis. Kahalalide V (1) was ascertained to be an acyclic derivative of kahalalide D (5), while kahalalide W (2) was determined to have a 4-hydroxy-l-proline residue instead of the proline in 5. The arginine residue of kahalalide X (3), an acyclic derivative of kahalalide C, was determined to have an l configuration. Kahalalide Y (4) was found to have an l-proline residue instead of the hydroxyproline in kahalalide K. It is clear from this collection of E. rufescens that the discovery of new kahalalide-related metabolites is still highly feasible.
Co-reporter:Anna J. Kochanowska, Karumanchi V. Rao, Suzanne Childress, Abir El-Alfy, Rae R. Matsumoto, Michelle Kelly, Gina S. Stewart, Kenneth J. Sufka and Mark T. Hamann
Journal of Natural Products 2008 Volume 71(Issue 2) pp:186-189
Publication Date(Web):January 25, 2008
DOI:10.1021/np070371u
Brominated indole alkaloids are a common class of metabolites reported from sponges of the order Verongida. Herein we report the isolation, structure determination, and activity of metabolites from three Florida sponges, namely, Verongula rigida (order Verongida, family Aplysinidae), Smenospongia aurea, and S. cerebriformis (order Dictyoceratida, family Thorectidae). All three species were investigated chemically, revealing similarities in secondary metabolites. Brominated compounds, as well as sesquiterpene quinones and hydroquinones, were identified from both V. rigida and S. aurea despite their apparent taxonomic differences at the ordinal level. Similar metabolites found in these distinct sponge species of two different genera provide evidence for a microbial origin of the metabolites. Isolated compounds were evaluated in the Porsolt forced swim test (FST) and the chick anxiety−depression continuum model. Among the isolated compounds, 5,6-dibromo-N,N-dimethyltryptamine (1) exhibited significant antidepressant-like action in the rodent FST model, while 5-bromo-N,N-dimethyltryptamine (2) caused significant reduction of locomotor activity indicative of a potential sedative action. The current study provides ample evidence that marine natural products with the diversity of brominated marine alkaloids will provide potential leads for antidepressant and anxiolytic drugs.
Co-reporter:Khalid A. El Sayed, Ashraf A. Khalil, Muhammad Yousaf, Guillermo Labadie, Gundluru M. Kumar, Scott G. Franzblau, Alejandro M. S. Mayer, Mitchell A. Avery and Mark T. Hamann
Journal of Natural Products 2008 Volume 71(Issue 3) pp:300-308
Publication Date(Web):January 17, 2008
DOI:10.1021/np0703702
Chemical transformation studies were conducted on (−)-8-hydroxymanzamine A (1), (−)-manzamine F (2), manzamine A (3), and (+)-8-hydroxymanzamine A (4), isolated from Indo-Pacific Acanthostrongylophora sponges.(1) Thirteen new semisynthetic manzamine derivatives, including four Δ34,35 manzamines (5, 6, 8, and 9) and the unprecedented manzamine derivative 17, are reported. The potent in vitro activities of the obtained semisynthetic manzamines against activated brain microglia and the AIDS opportunistic infection pathogen Mycobacterium tuberculosis are presented.
Co-reporter:Marwa S. Donia, Bin Wang, Daniel C. Dunbar, Prashant V. Desai, Akshay Patny, Mitchell Avery and Mark T. Hamann
Journal of Natural Products 2008 Volume 71(Issue 6) pp:941-945
Publication Date(Web):June 11, 2008
DOI:10.1021/np700718p
Two new cyclic hexapeptides, mollamides B (1) and C (2), were isolated from the Indonesian tunicate Didemnum molle along with the known peptide keenamide A (3). The structures were established using 1D and 2D NMR experiments. The relative configuration of mollamide B at the thiazoline moiety was determined using molecular modeling coupled with NMR-derived restraints. Their absolute configuration was determined using Marfeyʼs method. The new peptides have been evaluated for their antimicrobial, antimalarial, anticancer, anti-HIV-1, anti-Mtb, and anti-inflammatory activities. Keenamide A and mollamide B show cytotoxicity against several cancer cell lines.
Co-reporter:John J. Bowling;Hari K. Pennaka;Kelly Ivey;Subagus Wahyuono;Michelle Kelly;Raymond F. Schinazi;Frederick A. Valeriote;David E. Graves;Mark T. Hamann
Chemical Biology & Drug Design 2008 Volume 71( Issue 3) pp:205-215
Publication Date(Web):
DOI:10.1111/j.1747-0285.2008.00628.x
Aaptamine has potent cytotoxicity that may be explained by its ability to intercalate DNA. Aaptamine was evaluated for its ability to bind to DNA to validate DNA binding as the primary mechanism of cytotoxicity. Based on UV–vis absorbance titration data, the Kobs for aaptamine was 4.0 (±0.2) × 103 which was essentially equivalent to the known DNA intercalator N-[2-(diethylamino)ethyl]-9-aminoacridine-4-carboxamide. Semi-synthetic core modifications were performed to improve the general structural diversity of known aaptamine analogs and vary its absorption characteristics. Overall, 26 aaptamine derivatives were synthesized which consisted of a simple homologous range of mono and di-N-alkylations as well as some 9-O-sulfonylation and bis-O-isoaaptamine dimer products. Each product was evaluated for activity in a variety of whole cell and viral assays including a unique solid tumor disk diffusion assay. Details of aaptamine’s DNA-binding activity and its derivatives’ whole cell and viral assay results are discussed.
Co-reporter:Mohamed A. Ibrahim, Abbas G. Shilabin, Sivaprakasam Prasanna, Melissa Jacob, Shabana I. Khan, Robert J. Doerksen, Mark T. Hamann
Bioorganic & Medicinal Chemistry 2008 Volume 16(Issue 14) pp:6702-6706
Publication Date(Web):15 July 2008
DOI:10.1016/j.bmc.2008.05.079
Quaternary carbolinium salts have been reported to show improved antimalarial activity and reduced cytotoxicity as compared to electronically neutral β-carbolines. In this study, mono- and di-methylated quaternary carbolinium cations of manzamine A were synthesized and evaluated for their in vitro antimalarial and antimicrobial activity, cytotoxicity, and also their potential for glycogen synthase kinase (GSK-3β) inhibition using molecular docking studies. Among the analogs, 2-N-methylmanzamine A (2) exhibited antimalarial activity (IC50 0.7–1.0 μM) but was less potent than manzamine A. However the compound was significantly less cytotoxic to mammalian kidney fibroblasts and the selectivity index was in the same range as manzamine A.Mono- and di-methylated quaternary carbolinium salts of manzamine A were synthesized and evaluated for their antimalarial activity and cytotoxicity and their potential bind with inhibit GSK-3β using docking. These modifications were made based on previous studies suggesting N-alkylation of β-carbolines improves malaria activity and reduces toxicity.
Co-reporter:Hui-ming Hua, Jiangnan Peng, Frank R. Fronczek, Michelle Kelly, Mark T. Hamann
Bioorganic & Medicinal Chemistry 2004 Volume 12(Issue 24) pp:6461-6464
Publication Date(Web):15 December 2004
DOI:10.1016/j.bmc.2004.09.026
Three tricyclic guanidine alkaloids, including 1,8a;8b,3a-didehydro-8β-hydroxyptilocaulin (1), 1,8a;8b,3a-didehydro-8α-hydroxyptilocaulin (2) and mirabilin B (3), were identified from the marine sponge Monanchora unguifera. 1,8a;8b,3a-Didehydro-8α-hydroxyptilocaulin (2) is a new stereoisomer of 1, the structure of which was elucidated by spectroscopic analysis, comparison of its spectral data with those of 1, and confirmed by X-ray analysis. Compounds 1 and 2 co-crystallized in an unusual perfect order and packed around an approximate inversion center. A mixture of 1 and 2 is active against the malaria parasite Plasmodium falciparum with an IC50 value of 3.8 μg/mL while mirabilin B (3) exhibited antifungal activity against Cryptococcus neoformans with an IC50 value of 7.0 μg/mL and antiprotozoal activity against Leishmania donovani with an IC50 value of 17 μg/mL.
Co-reporter:Amanda L Waters, Russell T Hill, Allen R Place, Mark T Hamann
Current Opinion in Biotechnology (December 2010) Volume 21(Issue 6) pp:780-786
Publication Date(Web):1 December 2010
DOI:10.1016/j.copbio.2010.09.013
Marine microbes have received growing attention as sources of bioactive metabolites and offer a unique opportunity to both increase the number of marine natural products in clinical trials as well as expedite their development. This review focuses specifically on those molecules currently in the clinical pipeline that are established or highly likely to be produced by bacteria based on expanding circumstantial evidence. We also include an example of how compounds from harmful algal blooms may yield both tools for measuring environmental change as well as leads for pharmaceutical development. An example of the karlotoxin class of compounds isolated from the dinoflagellate Karlodinium veneficum reveals a significant environmental impact in the form of massive fish kills, but also provides opportunities to construct new molecules for the control of cancer and serum cholesterol assisted by tools associated with rational drug design.
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