NMR study of cyclic peptides with renin inhibitor activity

Several cyclic analogues of renin inhibitors, based on Glu-D-Phe-Lys motif have been investigated by NMR spectroscopy and molecular dynamics calculations (MD). The 15 membered macrocycle, resulting from Glu and Lys side-chain cyclization, exhibits conformational preference. The structural evidence from NMR shows the presence of hydrogen bond between Lys NH and Glu side-chain carbonyl, resulting in a 10 membered pseudo beta-turn-like structure. The structure of the cyclic moiety is similar in all the peptides, which takes at least two conformations around Calpha-Cbeta in Glu side chain. The restrained MD calculations further support such observations and show that the macrocycle is fairly rigid, with two conformations about the Glu Calpha-Cbeta bond. The linear peptide appendages, which are essential for activity in cyclic peptides, show an extended structure in the beta-region of Ramchandran plot. These calculations also demonstrate that for the most active peptide, two major conformers each exist about the Calpha-CO bond of the Lys, D-Trp and Leu residues. In this peptide, the cyclic moiety presents a negatively charged surface formed due to the carbonyl oxygens, which are thus available to form hydrogen bonds with the receptor. The linear fragment presents further binding sites with a surface which has the hydrophobic side chains of D-Trp, Leu and D-Met on one side and carbonyls on the other side.     

Potential of Mauritius Hemp (Furcraea gigantea Vent.) for the Remediation of Chromium Contaminated Soils

The present study was conducted to evaluate the ability of a high biomass producing, drought tolerant succulent plant Mauritius hemp (Furcraea gigantea Vent.) for its tolerance to different levels of Cr (0, 25, 50, 100 and 200 mg Cr kg soil^?1) and its potential for phytoremediation purposes. Based on the data on inhibition of the growth of plants with Cr, tolerance index and grade of growth inhibition, it was observed that the plant could tolerate up to 50 mg Cr kg ^?1 soil. Absorption of Cr from soil to plant and its translocation into plant tissues were discussed in terms of bio concentration factor (BCF), transfer factor (TF), and translocation efficiency (TE%). Cr was mainly accumulated in the roots and exclusion of Cr was found to be the principal physiological tolerance mechanism followed by a marked increase in proline, ascorbic acid, total free amino acids in the leaf tissue and malic acid in the rhizosphere samples to counter Cr stress. Based on the tissue concentration of Cr (< 300 μg g^?1 in the leaves and TF<1), it was concluded that, Furcraea gigantea could not be considered a hyperaccumulator and therefore unsuitable for phytoextraction of Cr. Nevertheless, Furcraea gigantea could be a suitable candidate for phytostablization of Cr contaminated soils.     

Tolerance of Ornamental Succulent Plant Crown of Thorns (Euphorbia milli) to Chromium and its Remediation

The potential of an ornamental shrub Crown of thorns (Euphorbia milli) was evaluated for remediation of soil contaminated with Cr. The plant is one of the rare succulent ornamental shrubs with a slow to moderate growth rate and is capable of blooming almost year-round. The plant could tolerate well up to 75 mg of applied Cr and beyond that there was mortality of plants. Though the plant could not be classified as a hyperaccumulator, the plant was still very efficient in translocating Cr from roots to shoots as evident from the data on uptake and translocation efficiency values. The translocation efficiency of over 80% in our study demonstrates that a large proportion of Cr has been translocated to the harvestable biomass of the plant and therefore, this plant could be effectively recommended for the remediation of soils contaminated with low to medium level of contamination i.e., up to 50 mg/kg soil.     

Cooperativity of Cdk4R24C and Ras in melanoma development

The importance of the Cdk4 protein in human cancer became evident following the identification of a germ line mutation in the Cdk4 locus that predisposes humans to melanoma. This mutation results in substitution of argininefirst with cysteine at position 24 (R24C). In an earlier study, we introduced the R24C mutation into the Cdk4 locus of mice using Cre-loxp-mediated “knock-in” technology and observed a very low incidence of spontaneous melanomas in Cdk4^R24C/R24C mice. This suggested that additional oncogenic mutations might be required for development of melanomas. Here we report an increased incidence of spontaneous cutaneous melanoma in mice expressing the oncogene HRAS(G12V) in melanocytes on a Cdk4^R24C background. Treatment of Tyr-HRas:Cdk4^R24C/R24C mice with the carcinogen, DMBA/TPA resulted in a further increase in the number of nevi and melanomas developed when compared with Tyr-HRas:Cdk4^+/+ mice. In summary, in Tyr-HRas:Cdk4^R24C/R24C mice, we observed that activated Cdk4 cooperates with the oncogenic HRAS(G12V) protein to increase the susceptibility of melanoma development in vivo.Key words: Cdk4^R24C, ras, melanoma, skin, carcinogen     

Rhodethrin: a novel indole terpenoid ether produced by Rhodobacter sphaeroides has cytotoxic and phytohormonal activities

A novel metabolite was isolated from the culture supernatants of Rhodobacter sphaeroides OU5 when grown on l-tryptophan as sole source of nitrogen under photoheterotrophic conditions. It was identified by IR, NMR (¹H, ¹³C) and MS as an indole terpenoid ether [3-hydroxy-6-(1H-indol-3-yloxy)-4-methylhexanoic acid] and is named as rhodethrin. Rhodethrin at 0.5 μM gave positive test in auxin bioassay and initiated early rooting in tissue-cultured plants than IAA at 5 μM. Rhodethrin has cytotoxic activity against Sup-T₁ lymphoma and Colo-125 cancer cell lines at 10 nM.     

Praziquantel derivatives I: Modification of the aromatic ring

Several analogues of the potent anthelmintic praziquantel were prepared with variation in the aromatic ring. The biological activity of these analogues was evaluated and compared against known analogues. Amination of the ring was tolerated while other variations were not. These results have important implications for drug development for schistosomiasis.     

Rhodestrin: A Novel Indole Terpenoid Phytohormone from Rhodobacter sphaeroides

A new phytohormone was isolated as a metabolite of anthranilate photobiotransformation by Rhodobacter sphaeroides OU5. It was identified by MS and NMR ((1)H, (13)C) as an indole terpenoid ester [(2E,4E,6E,8E,10E,12E,14E,16E,18E)24-hydroxy-2,6,10,14,19 pentamethyl tetrecosa-2,4,6,8,10,12,14,16,18 nonenyl-2(hydroxy methyl)-1H-indole-3-carboxylate] and is named as rhodestrin. Rhodestrin at 50 nM: gave positive test in auxin bioassay and initiated more profuse and early rooting in tissue-cultured plants than other auxins at 5 microM.