Aqua mediated synthesis of substituted 2-amino-4H-chromenes and in vitro study as antibacterial agents

A simple, clean, environmentally benign route to the synthesis of 2-amino-chromenes is described using K2CO3 as a green catalyst in water under microwave irradiation. This implies a convenient route avoiding the usage of hazardous organic solvents and organic bases. This technique requires only water in both the reaction step and workup, thus rendering the whole procedure into a truly ecofriendly green protocol. All the synthesized compounds were shown to possess antibacterial activity as tested in vitro against standard strains of Escherichia coli, Pseudomonas aeruginosa, and Staphylococcus aureus.     

Anti-influenza activity of monoterpene-derived substituted hexahydro-2H-chromenes

The antiviral activity of 4-hydroxy-hexahydro-2H-chromenes and 4-fluorine-hexahydro-2H-chromenes with an aromatic substituent, synthesized from monoterpene (−)-verbenone, was studied for the first time. Five of 11 (45 per cent) of 4-hydroxy-hexahydro-2H-chromene-type compounds have been found to exhibit antiviral activity against influenza A virus of subtype H1N1pdm09. Although a portion of active compounds among 4-fluorine-containing series was fewer, just compound 5i that contains a fluorine substituent exhibited more potent anti-influenza activity along with low cytotoxicity. Thus two new promising types of antiviral compounds were identified.     

Synthesis and anti-rhinovirus activity of novel 3-[2-(pyridinyl)vinyl]substituted -2H-chromenes and -4H-chromen-4-ones

Human rhinoviruses (HRVs) are the most common cause of viral respiratory infections and their complications. So far, no anti-viral agent has been approved for prevention or treatment of HRV infections. Pursuing our researches on small molecules with anti-rhinovirus activity, in this paper we describe the synthesis and in vitro anti-HRV 1B and 14 properties of new [2-(2H-chromen-3-yl)vinyl]pyridines and 3-[2-(pyridinyl)vinyl]-4H-chromen-4-ones. Generally, the synthesized compounds interfered with the replication of both serotypes at the micromolar or submicromolar concentrations. Preliminary results on their mechanism of action, performed on selected (E)-2-[2-(2H-chromen-3-yl)vinyl]pyridine, indicate an interference with the early step(s) of HRV 1B and 14 replication, probably at the uncoating level.     

Kinetics of the exchange reaction catalyzed by 2-amino-3-ketobutyrate CoA ligase

2-Amino-3-ketobutyrate CoA ligase (KBL) of Escherichia coli is a member of the α-oxoamine synthase family; it catalyzes the condensation reaction between glycine and acetyl CoA to yield 2-amino-3-ketobutyrate.We have previously shown that KBL catalyzes the exchange of pro-R hydrogen of glycine with protons in the medium; however, the kinetics of this reaction has never been determined. In this study, we calculated the kinetic parameters of this exchange reaction by using different concentrations of [2RS- ³H₂: 2-¹⁴C] glycine. The rate of the exchange reaction was determined by measuring the ³H/¹⁴C ratio in recovered [2S- ³H: 2-¹⁴C]glycine. The Lineweaver-Burk plot showed that K _m and k _cat of this reaction were 3.8 × 10^-3 M and 0.22 S^-1, respectively. On the other hand, K _m and k _cat values of the overall KBL-mediated catalysis were correspondingly 1.23 × 10^-2M and 1.19 S^-1. Thus, the rate of the exchange reaction was almost five times lower than that of overall KBL catalysis.     

Highly efficient synthesis of vinyl substituted triazoles by Au(I) catalyzed alkyne activation

Au(I) catalyzed 1,2,3-triazole addition to non-activated alkyne was reported. A large group of substituted NH-1,2,3-triazoles were suitable for this transformation along with both internal and terminal alkynes. The N-1 and N-2 vinyl substituted 1,2,3-triazoles were prepared in up to 98% yield with as low as 0.2% catalyst loading, thereby providing a new protocol for the synthesis of potentially biological-active vinyl-triazole building blocks.     

Enantioselective synthesis of (S)-2-amino-4-phenylbutanoic acid by the hydantoinase method

Biosynthesis of (S)-(+)-2-amino-4-phenylbutanoic acid (1) was performed by nonenantioselective hydantoinase and L-N-carbamoylase using racemic 5-[2-phenylethyl]-imidazolidine-2,4-dione (rac-2) as a substrate. The compounds involved in this biocatalysis process could be simultaneously resolved by high-performance liquid chromatography using Chirobiotic T column with a mobile phase of EtOH/H(2)O = 10/90 at pH 4.2-4.5. To our knowledge, this is the first report of the successful production of 1 by the combination of recombinant hydantoinase and L-N-carbamoylase.     

A lipase‐catalyzed process for green synthesis of temsirolimus

Temsirolimus is an intravenous drug for the treatment of renal cell carcinoma that can be prepared using enol acyl donors, which is not favorable in process development. An improved enzymatic process to prepare temsirolimus has been developed employing lipase‐catalyzed regioselective acylation of rapamycin with environmentally friendly acyl donors. After screening of common commercial lipases and none‐enol acyl donors, it was found that p‐nitrophenyl 2,2,5‐trimethyl‐1,3‐dioxane‐5‐carboxylate reacted as efficient acyl donor when catalyzed by immobilized Thermomyces lanuginose lipase. By optimizing the process conditions (i.e., reaction temperature, solvents, and additives), the reaction time was significantly shortened while the reaction conversion reached 95.4% in methyl tert‐butyl ether after 48 h at 50°C using the new acyl donors. This work demonstrated a cost‐effective, efficient, and scalable process to synthesize temsirolimus.     

Convenient synthesis of 8-amino-2'-deoxyadenosine

We studied the behaviour of 8-azido-2'-deoxyadenosine and 8-bromo-2'-deoxyadenosine in aqueous solutions of ammonia and primary and secondary amines. Unexpectedly, 8-Azido-2'-deoxyadenosine is converted to 8-amino-2'-deoxyadenosine in excellent yields. The use of this reaction for the preparation of 8-aminoadenine derivatives needed for the preparation of oligonucleotides carrying 8-aminoadenine is discussed.     

Template-directed synthesis of oligoadenylates catalyzed by Pb2+ ions

The Pb2+ ion is an effective catalyst for the template-directed condensation of ImpA on poly(U). This reaction generates up to 35% of oligomers 5 or more units long. Furthermore, the product is predominantly 3'-5'-linked (75%) unlike that from the uncatalyzed reaction which is more than 90% 2'-5'-linked. The significance of metal-ion catalysis for prebiotic polynucleotide formation is discussed.     

Design,synthesis and antiproliferative activity of novel substituted 2-amino-7,8-dihydropteridin-6(5H)-one derivatives

Based on our previous work, a series of novel 2-amino-7,8-dihydropteridin-6(5H)-one derivatives were designed and synthesized via a ring-closing strategy. Biological evaluation with four human cancer cell lines (BT549, T47D, MDA-MB-468, and MDA-MB-231) showed that most of these compounds possessed moderate to potent antiproliferative activities. The most promising compound 8-benzyl-2-(phenethylamino)-7,8-dihydropteridin-6(5H)-one (6q) possessing IC₅₀ values of 7.75, 6.37, and 10.73 μM against MDA-MB-468, T47D, and BT549, respectively, which were 49, 11, and 8 folds more active than the positive control fluorouracil. Moreover, fluorescence-activated cell sorting analysis revealed that compound 6q displayed a significant effect on G1 cell-cycle arrest in a concentration-dependent manner in T47D cells. The initial structure–activity relationship studies indicated that linker-length of amine chain in C-2 position of pyrimidine ring played a crucial role in modulating the antitumor activity, which could be of help in the rational design of dihydropteridin-6(5H)-ones as novel anticancer drugs.     

The synthesis of diosgenyl 2-amino-2-deoxy-beta-D-glucopyranoside hydrochloride

The N-trifluoroacetyl- and N-tetrachlorophthaloyl-protected bromide of D-glucosamine has been used for the first time as a glycosyl donor for the glycosylation of diosgenin [(25R)-spirost-5-en-3beta-ol]. Both 1,3,4,6-tetra-O-acetyl-2-deoxy-2-trifluoroacetamido-beta-D-glucopy ranoside and 1,3,4,6-tetra-O-acetyl-2-deoxy-2-tetrachlorophthalimido-alpha,beta -D-glucopyranoside were transformed into the appropriate glycosyl bromides. These reacted with diosgenin under mild conditions, using silver triflate as a promoter, and gave the corresponding protected diosgenyl glycosides. Each was deprotected to give diosgenyl 2-amino-2-deoxy-beta-D-glucopyranoside hydrochloride. The structures of the new glycosides were established by 1H NMR spectroscopy.     

Design and synthesis of 4-amino-2-phenylquinazolines as novel topoisomerase I inhibitors with molecular modeling

4-Amino-2-phenylquinazolines 7 were designed as bioisosteres of 3-arylisoquinolinamines 6 that were energy minimized to provide stable conformers. Interestingly, the 2-phenyl ring of 4-amino-2-phenylquinazolines was parallel to the quinazoline ring and improved their DNA intercalation ability in the DNA-topo I complex. Among the synthesized 4-amino group-substituted analogs, 4-cyclohexylamino-2-phenylquinazoline 7h exhibited potent topo I inhibitory activity and strong cytotoxicity. Interestingly, consistency was observed between the cytotoxicities and topo I activities in these quinazoline analogs, suggesting that the target of 4-amino-2-phenylquinazolines is limited to topo I. Molecular docking studies were performed with the Surflex-Dock program to afford the ideal interaction mode of the compound into the binding site of the DNA-topo I complex in order to clarify the topo I activity of 7h.     

Discovery and SAR of 4-amino-2-biarylbutylurea MCH 1 receptor antagonists through solid-phase parallel synthesis

-4-Amino-2-arylbutylbenzamides such as 1 were identified as micromolar MCH 1 receptor (MCH1R) antagonists via screening using a scintillation proximity assay based on [125I]-MCH binding to recombinant, human MCH1R. Subsequent lead optimization efforts using solid-phase parallel synthesis resulted in the defined structure-activity relationships and the identification of 4-amino-2-biarylbutylureas, such as 11g, as potent single digit nanomolar MCH1R antagonists.     

Inhibition of phytochrome synthesis by the transaminase inhibitor, 4-amino-5-fluoropentanoic Acid

Gardner and Gorton (1985 Plant Physiol 77: 540-543) demonstrated that the transaminase inhibitor gabaculine (5-amino-1,3-cyclohexadienyl-carboxylic acid) inhibits the initial synthesis and resynthesis of spectrophotometrically detectable phytochrome in vivo. Another mechanism-based transaminase inhibitor, 4-amino-5-fluoropentanoic acid (AFPA), is examined in this report for its effects on phytochrome synthesis in developing etiolated seedlings. Preemergence treatment with AFPA was found to inhibit initial phytochrome synthesis in peas (Pisum sativum L.), corn (Zea mays L.), and oats (Avena sativa L.). In general, reduction in phytochrome correlated with reduction in chlorophyll. However, the extent of inhibition of phytochrome synthesis was not as great as that of chlorophyll synthesis. These results confirm those with gabaculine, indicating that both initial synthesis and resynthesis of phytochrome require de novo synthesis of chromophore as well as apoprotein. AFPA was a more effective inhibitor of both chlorophyll and phytochrome synthesis than was gabaculine, suggesting that AFPA may be the preferred tool with which to probe the physiological consequences of the inhibition of phytochrome biosynthesis.