[Show abstract][Hide abstract] ABSTRACT: In order to produce a novel keto-carotenoid in Escherichia coli, we introduced the marine bacterial carotenoid ketolase gene (crtW) into pathway-engineered E. coli producing carotenoids of plant origin, which carried the lycopene biosynthesis genes (crtE, crtB, and crtI) from soil bacterium Pantoea ananatis and the liverwort Marchantia polymorpha genes that encode lycopene β-cyclase (MpLCYb), lycopene ε-cyclase (MpLCYe), and β-carotenoid hydroxylase (MpBHY). A novel keto-carotenoid (1) was produced by these carotenoid biosynthesis genes in E. coli along with α-echinenone, adonirubin, and adonixanthin. The structure of 1 was determined as (3S,6′R)-3-hydroxy-β,ε-caroten-4-one based on Uv–vis, MS, 1H NMR, and CD spectral data. This compound was named 4-ketozeinoxanthin and showed anti-tumor-promoting activity.
[Show abstract][Hide abstract] ABSTRACT: A new and efficient total synthesis has been developed to obtain plagiochin G (22), a macrocyclic bisbibenzyl, and four derivatives. The key 16-membered ring containing biphenyl ether and biaryl units was closed via an intramolecular SNAr reaction. All synthesized macrocyclic bisbibenzyls inhibited Epstein–Barr virus early antigen (EBV-EA) activation induced by the tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) in Raji cells and, thus, are potential cancer chemopreventive agents.
[Show abstract][Hide abstract] ABSTRACT: Nine limonoids, 1–9, one apocarotenoid, 11, one alkaloid, 12, and one steroid, 13, from the leaf extract; and one triterpenoid, 10, five steroids, 14–18, and two flavonoids, 19 and 20, from the bark extract of Melia azedarach L. (Chinaberry tree; Meliaceae) were isolated. Among these compounds, three compounds, 4–6, were new, and their structures were established as 3-deacetyl-28-oxosalannolactone, 3-deacetyl-28-oxosalanninolide, and 3-deacetyl-17-defurano-17,28-dioxosalannin, respectively, on the basis of extensive spectroscopic analyses and comparison with literature data. All of the isolated compounds were evaluated for their cytotoxic activities against leukemia (HL60), lung (A549), stomach (AZ521), and breast (SK-BR-3) cancer cell lines. 3-Deacetyl-4′-demethyl-28-oxosalannin (3) against HL60 and AZ521 cells, and methyl kulonate (10) against HL60 cells exhibited potent cytotoxicities with IC50 values in the range of 2.8–5.8 μM. In addition, upon evaluation of compounds 1–13 against production of nitric oxide (NO) in mouse macrophage RAW 264.7 cells induced by lipopolysaccharide (LPS), seven, i.e., trichilinin B (1), 4, ohchinin (7), 23-hydroxyohchininolide (8), 21-hydroxyisoohchininolide (9), 10, and methyl indole 3-carboxylate (12), inhibited production of NO with IC50 values in the range of 4.6–87.3 μM with no, or almost no, toxicity to the cells (IC50 93.2–100 μM). Western blot analysis revealed that compound 7 reduced the expression levels of the inducible NO synthase (iNOS) and COX-2 proteins in a concentration-dependent manner. Furthermore, compounds 5, 6, 13, and 18–20 exhibited potent inhibitory effects (IC50 299–381 molar ratio/32 pmol TPA) against EpsteinBarr virus early antigen (EBV-EA) activation induced by 12-O-tetradecanoylphorbol-13-acetate (TPA) in Raji cell line.
[Show abstract][Hide abstract] ABSTRACT: Compared to the current knowledge on cancer chemotherapeutic agents, only limited information is available on the ability of organic compounds, such as drugs and/or natural products, to prevent or delay the onset of cancer. In order to evaluate chemical chemopreventive potentials and design novel chemopreventive agents with low to no toxicity, we developed predictive computational models for chemopreventive agents in this study. First, we curated a database containing over 400 organic compounds with known chemoprevention activities. Based on this database, various random forest and support vector machine binary classifiers were developed. All of the resulting models were validated by cross validation procedures. Then, the validated models were applied to virtually screen a chemical library containing around 23,000 natural products and derivatives. We selected a list of 148 novel chemopreventive compounds based on the consensus prediction of all validated models. We further analyzed the predicted active compounds by their ease of organic synthesis. Finally, 18 compounds were synthesized and experimentally validated for their chemopreventive activity. The experimental validation results paralleled the cross validation results, demonstrating the utility of the developed models. The predictive models developed in this study can be applied to virtually screen other chemical libraries to identify novel lead compounds for the chemoprevention of cancers.
Journal of Computer-Aided Molecular Design 05/2014; · 3.17 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Two of each semisynthetic lanostane- and cycloartane-type triterpenes with a cyano-enone functionality, i.e., 13 and 18, and 23 and 28, respectively, sixteen of their synthetic intermediates, 9–12, 14–17, 19–22, and 24–27, along with seven semisynthetic oxygenated triterpene acetates, 29–35, and eight natural hydroxy triterpenes, 1–8, were evaluated for their cytotoxic activities against leukemia (HL60), lung (A549), stomach (AZ521), and breast (SK-BR-3) cancer cell lines. One natural triterpene, 8, and ten semisynthetic triterpenes, 9, 13, 15, 18, 23, 25, 28, 29, 32, and 33, exhibited potent cytotoxicities against one or more cell lines with IC50 values in the range of 1.4–9.9 μM. Two lanostane-type triterpenes with a cyano-enone functionality, 3-oxolanosta-1,8,24-triene-2-carbonitrile (13) and 3-oxolanosta-1,8-diene-2-carbonitrile (18), induced apoptosis in HL60 cells, as observed by membrane phospholipid exposure in flow cytometry. Western blot analysis showed that 13 and 18 significantly reduced procaspases-3, -8, and -9, and increased cleaved caspases-3, -8, and -9. These findings indicated that compounds 13 and 18 induced apoptosis in HL60 cells via both the mitochondrial and the death receptor-mediated pathways. In addition, upon evaluation of the inhibitory effects on EpsteinBarr virus early antigen (EBV-EA) activation induced with 12-O-tetradecanoylphorbol-13-acetate (TPA) in Raji cells, seven natural triterpenes, 1–6 and 8, and ten semisynthetic triterpenes, 9, 10, 14, 15, 19, 20, 24, 25, 29, and 30, exhibited inhibitory effects which were higher than that of β-carotene, a vitamin A precursor studied widely in cancer-chemoprevention animal models.
[Show abstract][Hide abstract] ABSTRACT: Seventeen limonoids (tetranortriterpenoids), 1–17, including three new compounds, i.e., 17-defurano-17-(2,5-dihydro-2-oxofuran-3-yl)-28-deoxonimbolide (14), 17-defurano-17-(2ξ-2,5-dihydro-2-hydroxy-5-oxofuran-3-yl)-28-deoxonimbolide (15), and 17-defurano-17-(5ξ-2,5-dihydro-5-hydroxy-2-oxofuran-3-yl)-2′,3′-dehydrosalannol (17), were isolated from an EtOH extract of the leaf of neem (Azadirachta indica). The structures of the new compounds were elucidated on the basis of extensive spectroscopic analyses and comparison with literature. Upon evaluation of the cytotoxic activities of these compounds against leukemia (HL60), lung (A549), stomach (AZ521), and breast (SK-BR-3) cancer cell lines, seven compounds, i.e., 1–3, 12, 13, 15, and 16, exhibited potent cytotoxicities with IC50 values in the range of 0.1–9.9 μM against one or more cell lines. Among these compounds, cytotoxicity of nimonol (1; IC50 2.8 μM) against HL60 cells was demonstrated to be mainly due to the induction of apoptosis by flow cytometry. Western blot analysis suggested that compound 1 induced apoptosis via both the mitochondrial and death receptor-mediated pathways in HL60 cells. In addition, when compounds 1–17 were evaluated for their inhibitory activities against melanogenesis in B16 melanoma cells, induced with α-melanocyte-stimulating hormone (α-MSH), seven compounds, 1, 2, 4–6, 15, and 16, exhibited inhibitory activities with 31–94% reduction of melanin content at 10 μM concentration with no or low toxicity to the cells (82–112% of cell viability at 10 μM). All 17 compounds were further evaluated for their inhibitory effects against the EpsteinBarr virus early antigen (EBV-EA) activation induced by 12-O-tetradecanoylphorbol-13-acetate (TPA) in Raji cells.
[Show abstract][Hide abstract] ABSTRACT: Graphical abstract
Ttriterpene glycosides and other polar compounds isolated from the extract of defatted shea (Vitellaria paradoxa; Sapotaceae) kernels exhibited inhibitory activities against melanogenesis, TPA-induced EBV-EA activation, and TPA-induced inflammation in mice, as well as DPPH free-radical-scavenging and cytotoxic activities.
[Show abstract][Hide abstract] ABSTRACT: The aqueous extract of Peltophorum pterocarpum (Fabaceae) wood exhibited potent inhibitory effects against EpsteinBarr virus early antigen (EBV-EA) activation induced with 12-O-tetradecanoylphorbol-13-acetate (TPA) in Raji cells and against melanogenesis in α-melanocyte-stimulating hormone (α-MSH)-stimulated B16 melanoma cells, as well as potent 1,1-diphenyl-2-picrylhydrazyl (DPPH) free radical-scavenging activity. Two phenolic acid derivatives, bergenin (1) and gallic acid (2), were isolated from the ethyl acetate (AcOEt)-soluble fraction obtained from the extract. Compound 1 exhibited potent inhibitory effect against EBV-EA activation and against skin tumor promotion in an in vivo two-stage mouse skin carcinogenesis test based on 7,12-dimethylbenz[a]anthracene (DMBA) as initiator, and with TPA as promoter. Both compounds 1 and 2 exhibited melanogenesis-inhibitory activities in α-MSH-stimulated B16 melanoma cells, and, in addition, compound 2 showed strong DPPH radical-scavenging activity.
[Show abstract][Hide abstract] ABSTRACT: A new flavonoid glycoside, chrysin 6-C-β-rutinoside (chrysin α-L-rhamnopyranosyl-(1→6)-C-β-glucopyranoside; 2), and two new triterpene glycosides, (31R)-31-O-methylpassiflorine (7) and (31S)-31-O-methylpassiflorine (8), along with 14 known glycosides, including three flavonoid glycosides, 1, 3, and 4, six triterpene glycosides, 5, 6, and 9-12, three cyano glycosides, 13-15, and two other glycosides, 16 and 17, were isolated from a MeOH extract of the leaves of Passiflora edulis (passion flower; Passifloraceae). The structures of new compounds were elucidated on the basis of extensive spectroscopic analysis and comparison with literature data. Upon evaluation of compounds 1-17 against the melanogenesis in the B16 melanoma cells induced with α-melanocyte-stimulating hormone (α-MSH), three compounds, isoorientin (1), 2, and (6S,9R)-roseoside (17), exhibited inhibitory effects with 37.3-47.2% reduction of melanin content with no, or almost no, toxicity to the cells (90.8-100.2% cell viability) at 100 μM. Western blot analysis showed that compound 2 reduced the protein levels of MITF, TRP-1, and tyrosinase, in a concentration-dependent manner while exerted almost no influence on the level of TRP-2, suggesting that this compound inhibits melanogenesis on the α-MSH-stimulated B16 melanoma cells by, at least in part, inhibiting the expression of MITF, followed by decreasing the expression of TRP-1 and tyrosinase. In addition, compounds 1-17 were evaluated for their inhibitory effects against the EpsteinBarr virus early antigen (EBV-EA) activation induced by 12-O-tetradecanoylphorbol-13-acetate (TPA) in Raji cells.
[Show abstract][Hide abstract] ABSTRACT: The cancer chemopreventive activity of quinoxaline derivatives 1-20 has been evaluated by studying the inhibitory effect on Epstein-Barr virus early antigen (EBV-EA) activation. The quinoxaline derivatives 1-20 showed inhibitory effect on EBV-EA activation without cytotoxicity on Raji cells. All compounds exhibited dose dependent inhibitory activities, most of them showed significant activity at 1000 mol ratio/12-O-tetradecanoylphorbol-13-acetate (TPA). Compounds 7 and 9 exhibited stronger inhibitory effects on the EBV-EA activation than that of the representative control, oleanolic acid, at the highest measured concentration. In addition, compounds 7-10 showed potent and selective inhibition of human tyrosine kinase (TRK) in liver cancer HepG2 and breast cancer MCF-7 cell lines similar to the positive control, doxorubicin.
European Journal of Medicinal Chemistry 08/2013; 69C:115-124. · 3.43 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Nine phenolic compounds, including two phenolic carboxylic acids, 1 and 2, seven hydrolyzable tannins, 3-9, eight triterpenoids, including four oleanane-type triterpene acids, 10-13, and four of their glucosides, 14-17, isolated from a MeOH extract of the gall of Terminalia chebula Retz. (myrobalan tree; Combretaceae), were evaluated for their inhibitory activities against melanogenesis in B16 melanoma cells induced by α-melanocyte-stimulating hormone (α-MSH), against the EpsteinBarr virus early antigen (EBV-EA) activation induced by 12-O-tetradecanoylphorbol 13-acetate (TPA) in Raji cells, and against TPA-induced inflammation in mice. Their 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical-scavenging activities and cytotoxic activities against four human cancer cell lines were also evaluated. Compounds 6-9 and 12 exhibited potent inhibitory activities against melanogenesis (39.3-66.3% melanin content) with low toxicity to the cells (74.5-105.9% cell viability) at a concentration of 10 μM. Western-blot analysis revealed that isoterchebulin (8) reduced the protein levels of MITF (=microphtalmia-associated transcription factor), tyrosinase, and TRP-1 (=tyrosine-related protein 1), mostly in a concentration-dependent manner. Eight triterpenoids, 10-17, showed potent inhibitory effects on EBV-EA induction with the IC50 values in the range of 269-363 mol ratio/32 pmol TPA, while these compounds exhibited no DPPH scavenging activities (IC50 >100 μM). On the other hand, the nine phenolic compounds, 1-9, exhibited potent radical-scavenging activities (IC50 1.4-10.9 μM) with weak inhibitory effects on EBV-EA induction (IC50 460-518 mol ratio/32 pmol TPA). The tannin 6 and seven triterpenoids, 10-16, have been shown to inhibit TPA-induced inflammation (1 μg/ear) in mice with the ID50 values in the range of 0.06-0.33 μmol/ear. Arjungenin (10) exhibited inhibitory effect on skin-tumor promotion in an in vivo two-stage mouse-skin carcinogenesis test based on 7,12-dimethylbenz[a]anthracene (DMBA) as initiator and with TPA as promoter. Compounds 1, 2, 4, 5, 7-9, 12, and 13, against HL60 cell line, compounds 1 and 4, against AZ521 cell line, and compounds 1, 11, and 12, against SK-BR-3 cell line, showed moderate cytotoxic activities (IC50 13.9-73.2 μM).
[Show abstract][Hide abstract] ABSTRACT: In continuation of our studies with chemoprevention potential of plant-derived naphthoquinone derivatives, leaf powder of the medicinal plant Lawsonia inermis L, commonly known as 'henna', was evaluated by its inhibition of the Epstein-Barr virus early antigen (EBV-EA) activation induced by the tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) in Raji cells. Lawsone (2-hydroxy-1,4-naphthoquinone), the reddish orange pigment artifact formed during the extraction or preparation of the dye from henna leaves and believed to be the active component, was also assessed in this in vitro assay. Both showed a profound inhibition (>88%) of EBV-EA activation. In the in vivo two-stage mouse skin carcinogenesis study using UV-B radiation for initiation and TPA for tumor promotion, oral feeding of henna (0.0025%) in drinking water ad libitum decreased tumor incidence by 66% and multiplicity by 40% when compared to the positive control at 10 weeks of treatment. Similarly, in the above mouse model, orally fed lawsone (0.0025%) decreased tumor incidence by 72% and multiplicity by 50%. The tumor inhibitory trend continued throughout the 20-week test period. Similar antitumor activities were observed when henna (0.5 mg/ml) was applied topically on the back skin in the UV-B initiated, TPA promoted and peroxynitrite initiated, TPA promoted mouse skin carcinogenesis models. Topically applied lawsone (0.015 mg/ml) also exhibited similar protection against tumor formation in the 7,12-dimtehylbenz(a)anthracene induced and TPA promoted skin cancer in mice. Also, there was a delay of 1 to 2 weeks in tumor appearance in both henna and lawsone treated groups compared to control in all three test models. This study ascertains the skin cancer chemopreventive activity of henna leaf powder and lawsone when administered by either oral (through drinking water) or topical (by application on the back skin) routes. Further, it emphasizes the need for the evaluation of these henna-derived green chemopreventive candidates in combination with currently used sunscreen agents for complementary anticancer potential against UV-induced skin carcinogenesis.
Anti-cancer agents in medicinal chemistry 06/2013;
[Show abstract][Hide abstract] ABSTRACT: Debromoaplysiatoxin (DAT) is a tumor promoter isolated from sea hare and exhibits anti-proliferative activity against several cancer cell lines. To clarify key residues that are responsible for its tumor-promoting activity, we focused on the chiral methoxy group in the side chain, whose role had not yet been discussed or examined before. Demethoxy-DAT (8) was derived from DAT and we evaluated its tumor-promoting activity, anti-proliferative activity, and ability to bind to protein kinase C (PKC) isozymes. Compound 8 showed somewhat weaker tumor-promoting activity than that of DAT both in vitro and in vivo, but showed higher anti-proliferative activity against several cancer cell lines. Although the affinity to novel PKC isozymes of 8 was comparable to that of DAT, the affinity to conventional PKC isozymes decreased slightly. These results suggest that the methoxy group of DAT is one of the key residues critical for tumor-promoting activity but not for anti-proliferative activity. Since the methoxy group has little influence on the molecular hydrophobicity, this is the first report showing that structural factors other than hydrophobicity in the side chain of DAT affected its biological activities.
[Show abstract][Hide abstract] ABSTRACT: Sunscreen compounds with added benefit of skin cancer prevention have both public and commercial interests. Our earlier study using the Epstein-Barr virus early antigen in vitro assay reported on skin cancer chemoprevention potential of benzophenone sunscreens. We now report the in vivo antitumor activity of two of the benzophenone sunscreens which tested positively in the in vitro assay, octabenzone (UV-1) and dioxybenzone (UV-2), in the two-stage mouse skin carcinogenesis model using (±)-(E)-4-methyl-2-[-(E)-hydroxyamino]-5-nitro-6-methoxy-3-hexanamide (NOR-1) as inducer and 12-O-tetradecanoyl-phorbol-13-acetate (TPA) as promoter.
Pathogen-free, female hairless mice of HOS:HR-1 strain, 15 animals per control and test groups, were used. Skin tumors were induced by a single dose of NOR-1 (390 nmol in 100 μl of acetone). One week later, TPA (1.7 nmol in 100 μl of acetone) was applied to skin twice weekly for 20 weeks as tumor a promoter. The test compounds UV-I or UV-2 were administered at 0.0025% to mice through drinking water ad libitum, starting one week prior to and stopping one week after tumor initiation. All animals were examined weekly for the development of skin papillomas.
In both UV-1- and UV-2-treated mice, a two-week delay in tumor appearance, and significant inhibition (p<0.001) of tumor incidence (50% and 60%, respectively) and tumor burden (papilloma inhibition/mouse, 50% and 70%, respectively) were observed when compared to the positive control group. UV-2 (dihydroxy derivative) was a more potent inhibitor of skin tumor than UV-1 (monohydroxy derivative), which followed their antioxidant activity ranking.
The results affirm the skin cancer chemoprevention potential of orally-ingested benzophenone sunscreens in mice and warrant studies in humans to validate synergistic protection achievable by complementation of oral and topical sunscreen usage.
Anticancer research 06/2013; 33(6):2535-40. · 1.71 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Morpholino-disiloxane (ALIS-409) and piperazino-disiloxane (ALIS-421) compounds were developed as inhibitors of multidrug resistance of various types of cancer cells. In the present study, the effects of ALIS-409 and ALIS-421 compounds were investigated on cancer promotion and on co-existence of tumor and normal cells. The two compounds were evaluated for their inhibitory effects on Epstein-Barr virus immediate-early antigen (EBV-EA) expression induced by tetradecanoyl-phorbol-acetate (TPA) in Raji cell cultures. The method is known as a primary screening test for antitumor effect, below the (IC50) concentration. ALIS-409 was more effective in inhibiting EBV-EA (100 μg/ml) and tumor promotion, than ALIS-421, in the concentration range up to 1000 μg/ml. However, neither of the compounds were able to reduce tumor promotion significantly, expressed as inhibition of TPA-induced tumor antigen activation. Based on the in vitro results, the two disiloxanes were investigated in vivo for their effects on mouse skin tumors in a two-stage mouse skin carcinogenesis study. The application of dimethyl-benzanthracene (DMBA; 390 nmol) as a tumor initiator was followed by exposure to TPA (1.7 nmol/l) as a tumor promoter. The experiments showed that ALIS-409 at a concentration of 85 nmol/l had a weak EBV-EA inhibitory effect in vitro and a moderate antitumor activity, compared to the positive control of DMBA plus TPA-treated mice. Flow cytometry by differential staining demonstrated interactions in co-cultures of MCF7 breast cancer and MRC5 human lung fibroblasts. The growth rate of tumor cells in mixed populations of MCF7 breast cancer and MRC5 normal fibroblast cells was reduced in the presence of ALIS-409, as compared to the control non-treated cell populations. The two disiloxanes were moderately-effective in chemoprevention in DMBA-induced and TPA-promoted in vivo tumor formation. Authors suggest that the inhibition of tumor cell and fibroblast interaction by ALIS409 might have some perspective in the development of anti-stromal therapy.
Anticancer research 05/2013; 33(5):2021-7. · 1.71 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Alkyl sophorosides, a special type of sophorolipids, can be produced using Candida bombicola cultures with glucose as main carbon source and 2-dodecanol as co-substrate. The dominating component, 2-dodecyl-sophoroside SL-E2-12, was purified via medium pressure liquid chromatography (MPLC) and used as substrate for further enzymatic modifications. Using β-glucuronidase in aqueous media the first modification gave a glycosidic cleavage of the acetyl glucose unit leading to 2-dodecyl-glucoside GL-A2-12. In a subsequent lipase-catalyzed acylation with sebacic acid in toluene this compound was functionalized regioselectively at the primary C-6′ position of glucose. Similar lipase-catalyzed reactions in toluene, but now using SL-E2-12 as acyl acceptor and unusual hydroxyl fatty acids – 3-hydroxy decanoic acid and 17-hydroxy stearic acid – as acyl donors, resulted in mono- and diacylations of primary hydroxyl positions of the sophorose unit (C-6′ and C-6′′) as shown by NMR and MS studies. In physicochemical characterization experiments the new glycoconjugates lowered the surface tension of water from 72 to 27–32 mN/m. Moreover it was observed that the new products inhibit the growth of particular Gram-positive bacteria. Additionally they indicate potential for anti-tumor promoting activity. Practical applications: According to literature data 2-alkyl-sophorosides can be produced using Candida bombicola cultures with yields of more than 20 g/L. Based on this starting material, 2-dodecyl-sophoroside, several regioselective enzymatic modifications were performed. Initially, β-glucuronidase catalysis in aqueous buffer solution gave 2-dodecyl-glucoside which was then successfully acylated at the C-6 position of glucose by lipase catalysis using a common dicarboxylic acid, sebacic acid. The resulting free carboxylic function of the acidic derivative opens up the possibility of achieving additional chemo-enzymatic reactions at this position for conversion, for instance, into polyesters. In addition lipase catalysis in organic solvents of 2-dodecyl-sophoroside allows acylation with unusual hydroxyl fatty acids of microbial origin. Physicochemical studies showed that these new glycoconjugates may be of interest for the cosmetic industry due to moisture conservation of the skin. For practical applications the conditions of the above biocatalytic reactions have been improved and scaled up.
European Journal of Lipid Science and Technology 04/2013; 115(4). · 2.27 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Culturing Pseudozyma aphidis on glucose as main carbon source and soybean oil as co-substrate the mannosylerythritol lipids MEL-A and MEL-B were produced. Based on their excellent surface/interfacial active behavior they possess a high potential among all known biosurfactants. The components of a microbial MEL mixture were purified by medium pressure liquid chromatography (MPLC) and were used as substrates for in vitro enzymatic modifications. Lipase-catalyzed acylations of MEL-A and MEL-B with uncommon fatty acids from other microbial glycolipids-3-hydroxydecanoic acid from rhamnolipids and 17-hydroxyoctadecanoic acid from classical sophorolipids-yielded functionalized products at the C-1 position of the erythritol. The novel products were purified by MPLC and their structures elucidated by (1)H and (13)C nuclear magnetic resonance spectroscopy and mass spectrometry. In physicochemical characterization experiments two of the three new glycoconjugates lowered the surface tension of water from 72mNm(-1) to 27-38mNm(-1). Moreover the novel compounds inhibited the growth of gram-positive bacteria and showed a potential for anti-tumor-promoting activity.
Carbohydrate research 03/2013; 373C:82-88. · 2.03 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We have recently developed a simplified analog of aplysiatoxin (aplog-1) as an activator of protein kinase C (PKC) with anti-proliferative activity like bryostain 1. To identify sites in aplog-1 that could be readily modified to optimize therapeutic performance and to develop a molecular probe for examining the analog's mode of action, substituent effects on the phenol ring were systematically examined. Whereas hydrophilic acetamido derivatives were less active than aplog-1 in inhibiting cancer cell growth and binding to PKCδ, introduction of hydrophobic bromine and iodine atoms enhanced both biological activities. The anti-proliferative activity was found to correlate closely with molecular hydrophobicity, and maximal activity was observed at a logP value of 4.0-4.5. On the other hand, an induction test with Epstein-Barr virus early antigen demonstrated that these derivatives have less tumor-promoting activity in vitro than aplog-1 regardless of the hydrophobicity of their substituents. These results would facilitate rapid preparation of molecular probes to examine the mechanism of the unique biological activities of aplog-1.