Stereoselective synthesis of a-Amino-C-phosphinic acids and derivatives

a-Amino-C-phosphinic acids and derivatives are an important group of compounds of synthetic and medicinal interest and particular attention has been dedicated to their stereoselective synthesis in recent years. Among these, phosphinic pseudopeptides have acquired pharmacological importance in influencing physiologic and pathologic processes, primarily acting as inhibitors for proteolytic enzymes where molecular stereochemistry has proven to be critical. This review summarizes the latest developments in the asymmetric synthesis of acyclic and phosphacyclic a-amino-C-phosphinic acids and derivatives, following in the first case an order according to the strategy used, whereas for cyclic compounds the nitrogen embedding in the heterocyclic core is considered. In addition selected examples of pharmacological implications of title compounds are also disclosed

Supramolecular phase-selective gelation by peptides bearing side-chain azobenzenes: Effect of ultrasound and potential for dye removal and oil spill remediation

Phase selective gelation (PSG) of organic phases from their non-miscible mixtures with water was achieved using tetrapeptides bearing a side-chain azobenzene moiety. The presence of the chromophore allowed PSG at the same concentration as the minimum gelation concentration (MGC) necessary to obtain the gels in pure organic phases. Remarkably, the presence of the water phase during PSG did not impact the thermal, mechanical, and morphological properties of the corresponding organogels. In the case of miscible oil/water mixtures, the entire mixture was gelled, resulting in the formation of quasi-hydrogels. Importantly, PSG could be triggered at room temperature by ultrasound treatment of the mixture or by adding ultrasound-aided concentrated solution of the peptide in an oil-phase to a mixture of the same oil and water. Moreover, the PSG was not affected by the presence of salts or impurities existing in water from natural sources. The process could be scaled-up, and the oil phases (e.g., aromatic solvents, gasoline, diesel fuel) recovered almost quantitatively after a simple distillation process, which also allowed the recovery and reuse of the gelator. Finally, these peptidic gelators could be used to quantitatively remove toxic dyes from aqueous solutions

Effect of Solvent Choice on the Self-Assembly Properties of a Diphenylalanine Amphiphile Stabilized by an Ion Pair

A diphenylalanine (FF) amphiphile blocked at the C terminus with a benzyl ester (OBzl) and stabilized at the N terminus with a trifluoroacetate (TFA) anion was synthetized and characterized. Aggregation of peptide molecules was studied by considering a peptide solution in an organic solvent and adding pure water, a KCl solution, or another organic solvent as co-solvent. The choice of the organic solvent and co-solvent and the solvent/co-solvent ratio allowed the mixture to be tuned by modulating the polarity, the ionic strength, and the peptide concentration. Differences in the properties of the media used to dissolve the peptides resulted in the formation of different self-assembled microstructures (e.g. fibers, branched-like structures, plates, and spherulites). Furthermore, crystals of TFAFF-OBzl were obtained from the aqueous peptide solutions for X-ray diffraction analysis. The results revealed a hydrophilic core constituted by carboxylate (from TFA), ester, and amide groups, and the core was found to be surrounded by a hydrophobic crown with ten aromatic rings. This segregated organization explains the assemblies observed in the different solvent mixtures as a function of the environmental polarity, ionic strength, and peptide concentration

Cysteine-based 3-substituted 1, 5-benzoxathiepin derivatives: Two new classes of anti-proliferative agents

Two distinct series of the 3-amino-1, 5-benzoxathiepin scaffold, derived from L-cysteine, were synthesized and evaluated for their anti-proliferative activity in the breast cancer MDA-MB-231 and MCF-7 cells, and in the ovarian carcinoma SKOV-3 cell line. (3R)-Amino-3, 4-dihydro-2H-1, 5-benzoxathiepin [(R)-10] was diversified into two forms: (a) by incorporating different amino acids at its position 3, through an amide bond; and (b) by construction of the purine ring to give 6-chloro-9-[2-(3, 4-dihydro-2H-1, 5-benzoxathiepin-(3R)-yl)]-9H-purine [(R)-28]. Nevertheless, when the introduction of iodine was tried at position 2 of the purine ring of (R)-28, 2-{[2-(6-chloro-2-iodo-9H-purin-9-yl) prop-2-en-1-yl] thio} phenol (34) was obtained. Compound 34 shows activity against cancer cells. Interestingly, 34 inhibits mammosphere formation at the micromolar range, demonstrating activity against cancer stem cells. Although further studies of its targets and mechanism of action are needed, these findings support the therapeutic potential of this compound in cancer

Short-term methane emissions from two dairy farms in California estimated by different measurement techniques and US Environmental Protection Agency inventory methodology: A case study

Atmospheric top-down measurements have attributed up to twice the methane (CH4) emissions of bottom-up (BU) inventories to dairy production. We explored this discrepancy by estimating CH4 emissions of two dairy facilities in California with U.S. Environmental Protection Agency (USEPA) methodology, which is used for BU inventories, and three independent measurement techniques: 1) open-path measurements with inverse dispersion modeling (hereafter “open-path”); 2) vehicle measurements with tracer flux ratio method; and 3) aircraft measurements with closed-path method. All three techniques estimated whole farm CH4 emissions during one week in the summer of 2016. In addition, open-path also estimated whole farm CH4 emissions during two months in the winter of 2017. The objectives of the present study were: 1) to compare the different techniques to measure whole farm CH4 emissions from dairies, 2) to estimate CH4 emissions from animal housing and liquid manure storage, and compare them to USEPA inventory estimates, and 3) to compare CH4 emissions between the two dairies. Whole farm CH4 estimates were similar among measurement techniques. No seasonality was detected for CH4 emissions from animal housing, but CH4 emissions from liquid manure storage were three to six times greater during the summer than during the winter. Open-path estimates for liquid manure storage emissions were similar to monthly USEPA estimates during the summer but not during the winter, and neither open-path estimates from summer nor winter were similar to the annual USEPA estimate. Thus, CH4 emissions need to be measured throughout the year to evaluate annual inventories. Methane yields from housing and liquid manure storage were used to compare emissions between the farms. While CH4 yields from animal housing were similar (on average 20.9 g CH4/kg dry matter intake), CH4 yields from liquid manure storage at one dairy were 1.7 and 3.5 times greater than at the other dairy during summer (234 vs. 137 g CH4/kg volatile solids [VS]) and winter (78 vs. 22 g CH4/kg VS), respectively. This greater CH4 yield was attributed to the greater proportion of manure stored in liquid form, which suggests that the promotion of manure management practices that reduce the amount of manure solids stored in liquid form, such as manure separators, could significantly reduce CH4 emissions from dairies. These results demonstrate that multiple techniques for monitoring emissions on these farms were comparable

(αMe)Nva: stereoselective syntheses and preferred conformations of selected model peptides

Using different stereoselective chemical and chemoenzymatic approaches we synthesized the chiral, Cα-methylated α-amino acid l-(αMe)Nva with a short, linear side-chain. A set of terminally protected model peptides to the pentamer level containing either (αMe)Nva or Nva in combination with Ala and/or Aib was prepared using solution methods and characterized fully. Two (αMe)Nva peptides were also synthesized using side-chain hydrogenation of the corresponding Cα-methyl, Cα-allylglycine (Mag) peptides. A detailed solution and crystal-state conformational analysis based on FT-IR absorption, 1H NMR and X-ray diffraction techniques allowed us to define that: (i) (αMe)Nva is an effective β-turn and 310-helix former; and (ii) the relationship between (αMe)Nva chirality and the screw sense of the turn/helix formed is that typical of protein amino acids, i.e. l-(αMe)Nva induces the preferential formation of right-handed folded structures. In more general terms, this study reinforced previous conclusions that peptides based on α-amino acids with a Cα-methyl substituent and a Cα-linear alkyl substituent are characterized by a strong tendency to fold into turn and helical structures.The Padova authors gratefully acknowledge M.U.R.S.T., the Ministry of University and Scientific and Technological Research, and C.N.R., the National Council of Research of Italy for their continuous support. The Zaragoza authors acknowledge the Direccion General de Investigacion Cientifica y Tecnica (PB94±0998) for financial support. The Zaragoza and Padova authors are also grateful to the Spain-Italy exchange program Accion Integrada HI 97-20/AzioniIntegrate 1997/99.Peer reviewe

A convenient route to optically pure α-alkyl-β-(sec-amino)alanines

The cyclization of N-Boc-α-alkylserines to corresponding β-lactones under Mitsunobu reaction conditions and the ring opening with heterocyclic amines (pyrrolidine, piperidine, morpholine and thiomorpholine) produced N-Boc-α-alkyl-β-(sec-amino)alanines. The removal of the Boc group gives di-hydrochlorides of non-protein amino acids

New (RS)-benzoxazepin-purines with antitumour activity: The chiral switch from (RS)-2,6-dichloro-9-[1-(p-nitrobenzenesulfonyl)-1,2,3,5-tetrahydro-4,1- benzoxazepin-3-yl]-9H-purine

Completing an SAR study, a series of (RS)-6-substituted-7- or 9-(1,2,3,5-tetrahydro-4,1-benzoxazepine-3-yl)-7H or 9H-purines has been prepared under microwave-assisted conditions. Their antiproliferative activities on MCF-7 and MDA-MB-231 cancerous cell lines are presented, being the majority of the IC50 values below 1 μM. The most active compound (RS)-2,6-dichloro-9-[1-(p-nitrobenzenesulfonyl)-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]-9H-purine (14) presents an IC50 of 0.166 μM against the human cancerous cell line MDA-MB-231. Compound 14 was the most selective against the human breast adenocarcinoma MCF-7 and MDA-MB-231 cancer cell lines (Therapeutic Indexes, TIs = 5.1 and 11.0, respectively) in relation to the normal one MCF-10A. (RS)-14 was resolved into its enantiomers. Both enantiomers are equally potent, but more potent than the corresponding racemic mixture. (R)-14 induces apoptosis against MCF-7 up to 52.50% of cell population after 48 h, being more potent than the clinical-used drug paclitaxel (43%). (RS)-14 induces no acute toxicity in mice after two weeks of treatment.This study was supported by the European Commission (A.C-G. Marie Curie Programme MERG-CT-2005-030616) and the Instituto de Salud Carlos III (Fondo de Investigación Sanitaria) through projects no. PI070227 and PI070527. The project “Factoría de Cristalización, CONSOLIDER INGENIO-2010” (CSD2006-00015) provided X-ray structural facilities for this work. We gratefully acknowledge the BM16 Spanish beamline at ESRF (Grenoble, France) for access to synchrotron radiation and for helpful assistance during data collection. D Ch-L thanks CSD2006-00015 for his research contract.Peer reviewe