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(4,4′-Bisfluorophenyl)methoxymethyl (BFPM) group of uridine ureido nitrogen shows good relative stability in a variety of chemical transformation reactions for uridine. The BFPM group can be cleaved by 2% of TFA in CH2Cl2 without affecting the Boc group.

The transforming growth factor-beta (TGF-β) pathway plays a paradoxical, context-dependent role in pancreatic ductal adenocarcinoma (PDAC): a tumor-suppressive role in non-metastatic PDAC and a tumor-promotive role in metastatic PDAC. We hypothesize that non-SMAD-TGF-β signaling induces PDAC progression. We investigated the expression of non-SMAD-TGF-β signaling proteins (pMAPK14, PD-L1, pAkt and c-Myc) in patient-derived tissues, cell lines and an immunocompetent mouse model. Experimental models were complemented by comparing the signaling proteins in PDAC specimens from patients with various survival intervals. We manipulated models with TGF-β, gemcitabine (DNA synthesis inhibitor), galunisertib (TGF-β receptor inhibitor) and MK-2206 (Akt inhibitor) to investigate their effects on NF-κB, β-catenin, c-Myc and PD-L1 expression. PD-L1 expression was also investigated in cancer cells and tumor associated macrophages (TAMs) in a mouse model. We found that tumors from patients with aggressive PDAC had higher levels of the non-SMAD-TGF-β signaling proteins pMAPK14, PD-L1, pAkt and c-Myc. In PDAC cells with high baseline β-catenin expression, TGF-β increased β-catenin expression while gemcitabine increased PD-L1 expression. Gemcitabine plus galunisertib decreased c-Myc and NF-κB expression, but induced PD-L1 expression in some cancer models. In mice, gemcitabine plus galunisertib treatment decreased metastases (p = 0.018), whereas galunisertib increased PD-L1 expression (p

A short total synthesis of tunicamycin V (1), a non-selective phosphotransferase inhibitor, is achieved via a Büchner–Curtius–Schlotterbeck type reaction. Tunicamycin V can be synthesized in 15 chemical steps from D-galactal with 21 % overall yield. The established synthetic scheme is operationally very simple and flexible to introduce building blocks of interest. The inhibitory activity of one of the designed analogues 28 against human dolichyl-phosphate N-acetylglucosaminephosphotransferase 1 (DPAGT1) is 12.5 times greater than 1. While tunicamycins are cytotoxic molecules with a low selectivity, the novel analogue 28 displays selective cytostatic activity against breast cancer cell lines including a triple-negative breast cancer.

We have explored a method to convert a muraymycin biosynthetic intermediate 3 to an anticancer drug lead 2 for in vivo and thorough preclinical studies. Cu(OAc)(2) forms a stable complex with the amide 4 and it prevents electrophilic reactions at the 2-((3-aminopropyl)amino)acetamide moiety. Under the present conditions, the desired 5”-primary amine was selectively protected with (Boc)(2)O to yield 6. The intermediate 6 was converted to 2 in two steps with 90% yield.

Capuramycin displays narrow spectrum of antibacterial activity by targeting bacterial translocase I (MraY). In our program of development of new N-acetylglucosaminephosphotransferase1 (DPAGT1) inhibitor, we have identified that a capuramycin phenoxypiperidinylbenzylamide analogue (CPPB) inhibits DPAGT1 enzyme with an IC(50) value of 200 nM. Despite a strong DPAGT1 inhibitory activity, CPPB does not show cytotoxicity against normal cells and a series of cancer cell lines. However, CPPB inhibits migrations of several solid cancers including pancreatic cancers that require high DPAGT1 expression in order for tumor progression. DPAGT1 inhibition by CPPB leads to a reduced expression level of Snail, but does not reduce E-cadherin expression level at the IC(50) (DPAGT1) concentration. CPPB displays a strong synergistic effect with paclitaxel against growth-inhibitory action of a patient-derived pancreatic adenocarcinoma, PD002: paclitaxel (IC(50) 1.25 μM) inhibits growth of PD002 at 0.0024–0.16 μM in combination with 0.10–2.0 μM of CPPB (IC(50) 35 μM).

Discovery of new anti-tuberculosis (TB) drugs is a time-consuming process due to the slow-growing nature of Mycobacterium tuberculosis (Mtb). A requirement of biosafety level 3 (BSL-3) facility for performing research associated with Mtb is another limitation for the development of TB drug discovery. In our screening of BSL-1 Mycobacterium spp. against a battery of TB drugs, M. smegmatis (ATCC607) exhibits good agreement with its drug susceptibility against the TB drugs under a low-nutrient culture medium (0.5% Tween 80 in Middlebrook 7H9 broth). M. smegmatis (ATCC607) enters its dormant form in 14 days under a nutrient-deficient condition (a PBS buffer), and shows resistance to a majority of TB drugs, but shows susceptibility to amikacin, capreomycin, ethambutol, and rifampicin (with high concentrations) whose activities against non-replicating (or dormant) Mtb were previously validated.

Mycobacterium tuberculosis (Mtb) uses a wide range of mechanisms to survive the host immune system. Mtb can persist in host tissues for months to decades without replicating, however, non-replicating (or dormant) Mtb has the ability to resume growth at any time. Persons with latent TB infection do not have typical TB symptoms, and dormant forms of Mtb are not considered transmissible. Several factors (e.g. HIV infection, cancers, and immunosuppressive drug therapy) alter the course of latent TB and are thought to have the potential to cause reactivation, leading to active TB. Treatment regimens for latent TB infection require long durations in order to prevent relapse. It is difficult to eradicate latent forms of the relatively drug resistant Mtb in short periods of time with the currently available TB therapies. Thus, it is very important to develop new drugs for the treatment of latent or persistent forms of Mtb that reduce treatment time required for TB patients. Mycobacterial cell walls consist of complex mixtures of polysaccharides and mycolic acids, and they play an important role in escaping from the host immune systems and in surviving within granulomas that form in response to the bacteria. This chapter reviews the potential drug targets that exist in cell wall biosynthesis for non-replicating (or dormant) Mtb based on bioinformatics, genomic and proteomic analyses and in vitro data with replicating and non-replicating bacilli.

Graphical abstract, Immunotherapy that targets N-linked glycans has not yet been developed due in large part to the lack of specificity of N-linked glycans between normal and malignant cells. N-Glycan chains are synthesized by the sequential action of glycosyl transferases in the Golgi apparatus. It is an overwhelming task to discover drug-like inhibitors of glycosyl transferases that block the synthesis of specific branching processes in cancer cells, killing tumor cells selectively. It has long been known that N-glycan biosynthesis can be inhibited by disruption of the first committed enzyme, dolichyl-phosphate N-acetylglucosaminephosphotransferase 1 (DPAGT1). Selective DPAGT1 inhibitors have the promising therapeutic potential for certain solid cancers that require increased branching of N-linked glycans in their growth progressions. Recently, we discovered that an anti-Clostridium difficile molecule, aminouridyl phenoxypiperidinbenzyl butanamide (APPB) showed DPAGT1 inhibitory activity with the IC50 value of 0.25 μM. It was confirmed that APPB inhibits N-glycosylation of β-catenin at 2.5 nM concentration. A sharp difference between APPB and tunicamycin was that the hemolytic activity of APPB is significantly attenuated (IC50 > 200 μM RBC). Water solubility of APPB is >350-times greater than that of tunicamycin (78.8 mg/mL for APPB, 60 min) for in vivo studies (PK/PD, safety profiles, and in vivo efficacy) using animal models. We have refined all steps in the previously reported synthesis for APPB for larger-scale. This article summarizes protocols of gram-scale synthesis of APPB and its physicochemical data, and a convenient DPAGT1 assay. • Remember that the abstract is what readers see first in electronic abstracting & indexing services. • This is the advertisement of your article. Make it interesting, and easy to be understood. • Be accurate and specific, keep it as brief as possible.

Glyceroacetonide-Oxyma [(2,2-dimethyl-1,3-dioxolan-4-yl)methyl 2-cyano-2-(hydroxyimino)acetate (1)] displayed remarkable physico-chemical properties as an additive for peptide-forming reactions. Although racemization-free amide-forming reactions have been established for N-urethane-protected α-amino acids with EDCI, 1, and NaHCO3 in water or DMF-water media, amide-forming reactions of N-acyl-protected α-amino acids and segment couplings of oligopeptides still require further development. Diethylphosphoryl-glyceroacetonide-oxyma (DPGOx 3) exhibits relative stability in aprotic solvents and is an effective coupling reagent for N-acyl-protected α-amino acids and oligo peptide segments. The conditions reported here is also effective in lactam-forming reactions. Unlike most of the reported coupling reagents, simple aqueous work-up procedures can remove the reagents and by-products generated in the reactions.

The spectrum of antibacterial activity for the nucleoside antibiotic FR-900493 (1) can be extended by chemical modifications. We have generated a small focused library based on the structure of 1 and identified UT-17415 (9), UT-17455 (10), UT-17460 (11), and UT-17465 (12), which exhibit anti-Clostridium difficile growth inhibitory activity. These analogues also inhibit the outgrowth of C. difficile spores at 2× minimum inhibitory concentration. One of these analogues, 11, relative to 1 exhibits over 180-fold and 15-fold greater activity against the enzymes, phospho-MurNAc-pentapeptide translocase (MraY) and polyprenyl phosphate-GlcNAc-1-phosphate transferase (WecA), respectively. The phosphotransferase inhibitor 11 displays antimicrobial activity against several tested bacteria including Bacillus subtilis, Clostridium spp., and Mycobacterium smegmatis, but no growth inhibitory activity is observed against the other Gram-positive and Gram-negative bacteria. The selectivity index (Vero cell cytotoxicity/C. difficileantimicrobial activity) of 11 is approximately 17, and 11 does not induce hemolysis even at a 100 μM concentration.

Multidrug-resistant (MDR) Acinetobacter baumannii is one of the most difficult Gram-negative bacteria to treat and eradicate. In a cell-based screening of pleuromutilin derivatives against a drug sensitive A. baumannii strain, new molecules (2–4) exhibit bacteriostatic activity with 3.13 μg/mL concentration and 1 shows bactericidal activity with an MBC of 6.25 μg/mL. The pleuromutilin derivative 1 displays strong synergistic effects with doxycycline in a wide range of concentrations. A 35/1 ratio of 1 and doxycycline (1-Dox 35/1) kills drug susceptible A. baumannii with the MBC of 2.0 μg/mL and an MDR A. baumannii with the MBC of 3.13 μg/mL. In vitro anti-Acinetobacter activity of 1-Dox 35/1 is superior to that of clinical drugs such as tobramycin, tigecycline, and colistin. The efficacy of 1-Dox 35/1 is evaluated in a mouse septicemia model; treatment of the infected C57BL/6 mice with 1-Dox 35/1 protects from lethal infection of A. baumannii with an ED50 value of

Capuramycin (1) and its analogs are strong translocase I (MurX/MraY) inhibitors. In our structure-activity relationship studies of capuramycin analogs against Mycobacterium tuberculosis (Mtb), we observed for the first time that a capuramycin analog, UT-01320 (3) killed nonreplicating (dormant) Mtb at low concentrations under low oxygen conditions, whereas selective MurX inhibitors killed only replicating Mtb under aerobic conditions. Interestingly, 3 did not exhibit MurX enzyme inhibitory activity even at high concentrations, however, 3 inhibited bacterial RNA polymerases with the IC50 values of 100-150 nM range. A new RNA polymerase inhibitor 3 displayed strong synergistic effects with a MurX inhibitor SQ 641 (2), a promising preclinical tuberculosis drug.

Translocase I (MraY/MurX) is an essential enzyme in growth of the vast majority of bacteria that catalyzes the transformation from UDP-MurNAc-pentapeptide (Park’s nucleotide) to prenyl-MurNAc-pentapeptide (lipid I), the first membrane-anchored peptidoglycan precursor. MurX has received considerable attention in the development of new tuberculosis (TB) drugs due to the fact that the MurX inhibitors kill exponentially growing Mycobacterium tuberculosis (Mtb) much faster than clinically used TB drugs. Lipid I isolated from Mtb contains the C50-prenyl unit that shows very poor water solubility; thus, this chemical characteristic of lipid I renders MurX enzyme assays impractical for screening and lacks reproducibility of the enzyme assays. We have established a scalable chemical synthesis of Park’s nucleotide-Ne-dansylthiourea 2 that can be used as a MurX enzymatic substrate to form lipid I analogues. In our investigation of the minimum structure requirement of the prenyl phosphate in the MraY/MurX-catalyzed lipid I analogue synthesis with 2, we found that neryl phosphate (C10 phosphate) can be recognized by MraY/MurX to generate the water-soluble lipid I analogue in quantitative yield under the optimized conditions. Here, we report a rapid and robust analytical method for quantifying MraY/MurX inhibitory activity of library molecules.

(2,6-Dichloro-4-methoxyphenyl)(2,4-dichlorophenyl)methyl trichloroacetimidate (3) and its polymer-supported reagent 4 can be successfully applied to a one-pot protection-glycosylation reaction to form the disaccharide derivative 7 d for the synthesis of lipid II analogues. The temporary protecting group or linker at the C-6 position and N-Troc protecting group of 7 d can be cleaved simultaneously through a reductive condition. Overall yields of syntheses of lipid II (1) and neryl-lipid II N(ε)-dansylthiourea are significantly improved by using the described methods.

The conventional method for quantitating Mycobacterium tuberculosis (Mtb) in vitro and in vivo relies on bacterial colony forming unit (CFU) enumeration on agar plates. Due to the slow growth rate of Mtb, it takes 3-6 weeks to observe visible colonies on agar plates. Imaging technologies that are capable of quickly quantitating both active and dormant tubercle bacilli in vitro and in vivo would accelerate research towards the development of anti-TB chemotherapies and vaccines. We have developed a fluorescent probe that can directly label the Mtb cell wall components. The fluorescent probe, designated as DLF-1, has a strong affinity to the D-Ala-D-Ala unit of the late peptidoglycan intermediates in the bacterial cell wall. We demonstrate that DLF-1 is capable of detecting Mtb in both the active replicating and dormant states in vitro at 100 nM without inhibiting bacterial growth. The DLF-1 fluorescence signal correlated well with CFU of the labeled bacteria (R2=1 and 0.99 for active replicating and dormant Mtb, respectively). DLF-1 can also quantitate labeled Mtb inside of cells. The utility of DLF-1 probe to quantitate Mtb was also successfully applied to identify genes critical for cell invasion. In conclusion, this novel near infrared imaging probe provides a powerful new tool for enumerating Mtb with potential future use in bacterial virulence study.

Capuramycin and its congeners have been considered important lead molecules for the development of a new drug for multidrug-resistant (MDR) Mycobacterium tuberculosis infections. Extensive structure-activity relationship studies of capuramycin to improve the efficacy have been limited due to difficulty in selective chemical modifications of the desired position(s) of the natural product with biologically interesting functional groups. We have developed efficient syntheses of capuramycin and its analogs using new protecting groups, which are derived from the chiral (chloro-4-methoxyphenyl) (chlorophenyl) methanols, for the uridine ureido nitrogen and primary alcohol. The chiral non-racemic (2,6-dichloro-4-methoxyphenyl) (2,4-dichlorophenyl) methanol derivative is a useful reagent to resolve rac-3-amino-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one, whose (S)-configuration isomer plays a significant role in improving the mycobactericidal activity of capuramycin.

We have realized that N-formylations of free amines of some drug leads can improve PK/PD property of parent molecules without decreasing their biological activities. In order to selectively formylate primary amines of polyfunctional molecules, we have sought a mild and convenient formylation reaction. In our screening of N-formylation of an α-amino acid, L-phenylalanine, none of formylation conditions reported to date yielded the desired HCO-L-Phe-OH with satisfactory yield. N-Formylations of amino acids with HCO2H require the reactions in a water-containing media and suppress polymerization reactions due to the competitive reactions among carboxylic acids. We found that N-formylations of α-amino acids could be achieved with a water-soluble peptide coupling additive, an oxyma derivative, (2,2-dimethyl-1,3-dioxolan-4-yl)methyl-2-cyano-2-(hydroxyimino)acetate (2), EDCI, and NaHCO3 in water or a mixture of water and DMF system, yielding N-formylated α-amino acids with excellent yields. Moreover, these conditions could selectively formylate primary amines over secondary amines at a controlled temperature. A usefulness of these conditions was demonstrated by selective formylation of daptomycin antibiotic which contains three different amino groups.

A stereocontrolled first total synthesis of muraymycin D1 (1) has been achieved. The synthetic route is highly stereoselective, featuring (1) selective β-ribosylation of the C2-methylated amino ribose, (2) selective Strecker reaction, and (3) ring-opening reaction of a diastereomeric mixture of a diaminolactone to synthesize muraymycidine (epi-capreomycidine). The acid-cleavable protecting groups for secondary alcohol and uridine ureido nitrogen are applied for simultaneous deprotections with the Boc and tBu groups. Muraymycin D1 (1) and its amide derivatives (2 and 3) exhibited growth inhibitory activity against Mycobacterium tuberculosis (MIC50 = 1.56–6.25 μg/mL) and strong enzyme inhibitory activities against the bacterial phosphotransferases (MurX and WecA) (IC50 = 0.096–0.69 μM).

Polyprenyl phosphate-GlcNAc-1-phosphate transferase (WecA) is an essential enzyme for the growth of Mycobacterium tuberculosis (Mtb) and some other bacteria. Mtb WecA catalyzes the transformation from UDP-GlcNAc to decaprenyl-P-P-GlcNAc, the first membrane-anchored glycophospholipid that is responsible for the biosynthesis of mycolylarabinogalactan in Mtb. Inhibition of WecA will block the entire biosynthesis of essential cell wall components of Mtb in both replicating and non-replicating states, making this enzyme a target for development of novel drugs. Here, we report a fluorescence-based method for the assay of WecA using a modified UDP-GlcNAc, UDP-Glucosamine-C6-FITC (1), a membrane fraction prepared from an M. smegmatis strain, and the E. coli B21WecA. Under the optimized conditions, UDP-Glucosamine-C6-FITC (1) can be converted to the corresponding decaprenyl-P-P-Glucosamine-C6-FITC (3) in 61.5% yield. Decaprenyl-P-P-Glucosamine-C6-FITC is readily extracted with n-butanol and can be quantified by ultraviolet–visible (UV–vis) spectrometry. Screening of the compound libraries designed for bacterial phosphotransferases resulted in the discovery of a selective WecA inhibitor, UT-01320 (12) that kills both replicating and non-replicating Mtb at low concentration. UT-01320 (12) also kills the intracellular Mtb in macrophages. We conclude that the WecA assay reported here is amenable to medium- and high-throughput screening, thus facilitating the discovery of novel WecA inhibitors.

Mycobacterium avium subspecies paratuberculosis (MAP) causes chronic illnesses mostly in ruminants. MAP infection of intestinal tissue triggers a fatal inflammatory disorder, Johne's disease (paratuberculosis). Development of fast and reliable diagnostic methods for Johne's disease in clinically suspected ruminants requires the discovery of MAP-specific antigens that induce immune responses. Despite a longtime interest in finding such antigens that can detect serum antibody responses with high sensitivity, the antigens currently used for a diagnosis of the MAP infections are the crude extracts from the whole cell. We performed the serum antibody response assay-guided purification of the ethanol extract from MAP isolated from an infected cow. With the results of extensive fractionations and in vitro assays, we identified that arachidyl- d -Phe- N -Me- l -Val- l -Ile- l -Phe- l -Ala-OH (named lipopeptide IIs, 3 ) exhibited the highest antibody binding activity in serum of a MAP-infected cattle compared with the other lipopeptides isolated from MAP. The absolute chemistry of 3 was determined unequivocally via our high-performance liquid chromatography (HPLC)–amino acid databases. α-Amino lipopeptide IIs and its fluorescent probes were synthesized and evaluated in serum antibody binding activity assays. Lipopeptide IIs-(2 S )-NH 2 ( 9 ) and its dansyl and fluorescein isothiocyanate (FITC) probes ( 10 and 11 ) exhibited antibody-mediated binding activity; thus, such MAP-specific lipopeptide probes can be potential biomarkers for the development of rapid and accurate diagnosis of Johne's disease.

Oxyma and an oxyma derivative, (2,2-dimethyl-1,3-dioxolan-4-yl)methyl 2-cyano-2-(hydroxyimino)acetate (5b), displayed a remarkable effect on selective esterifications of primary alcohols. A wide range of carboxylic acids could be esterified with primary alcohols by using EDCI, NaHCO(3), and Oxyma or Oxyma derivative 5b in 5% H(2)O-CH(3)CN. Oxyma derivative 5b is particularly useful, since it could be removed after the reaction via a simple basic or an acidic aqueous workup procedure.

An Oxyma derivative, (2,2-dimethyl-1,3-dioxolan-4-yl)methyl 2-cyano-2-(hydroxyimino)acetate (2), displayed remarkable physicochemical properties as a peptide-coupling additive for peptide-forming reactions in water. Short peptides to oligopeptides could be synthesized by using 2, EDCI, and NaHCO(3) in water without measurable racemization. Significantly, a simple basic and acidic aqueous workup procedure can remove all reagents utilized in the reactions to afford only coupling products in consistently excellent yields.

(2,6-Dichloro-4-methoxyphenyl) (2,4,6-trichlorophenyl) methoxymethyl chloride [1, monomethoxydiphenylmethoxylmethyl chloroide (MDPM-Cl)] shows a significant relative stability and 1 reacts with uridine ureido nitrogen in the presence of DBU to form the corresponding protected uridine 8 in 95% yield. The MDPM-protected uridines are stable to a wide variety of conditions utilized for the synthesis of analogs of capuramycin and muraymycins. Significantly, the MDPM protecting group can conveniently be deprotected by using 30% TFA in CH(2)Cl(2). In addition, polymer-bound MDPM-Cl 23 is useful for immobilization of uridine derivatives.

(2,6-Dichloro-4-methoxyphenyl)-(2,4-dichlorophenyl)-methyl trichloroacetimidate can be efficiently activated by TMSOTf (10∼100 mol%) to react with alcohols and carboxylic acids. Under these conditions a wide variety of alcohols can be transformed into the corresponding ethers in excellent yields with a slight excess of the trichloroacetimidate. The resulting ethers are not susceptible to typical deprotection conditions for benzyl and 4-methoxybenzyl ether groups, however, they can be conveniently deprotected by treatment with 30∼50% trifluoroacetic acid in dichloromethane. Polymer-bound (2,6-dichloro-4-alkoxyphenyl)-(2,4-dichlorophenyl)methyl trichloroacetimidate is useful for immobilization of alcohols and carboxylic acids.

Potent inhibitors of MenA (1,4-dihydroxy-2-naphtoate prenyltrasferase) in Mycobacterium tuberculosis are identified, and are also effective in inhibiting growth of Mycobacterium tuberculosis at low concentrations. The MenA inhibitors possess common chemical structural features of (alkylamino)oalkoxyphenyl)(phenyl)methanones. Significantly, the MenA inhibitors can be synthesized in a few steps with high overall yields. The representative MenA inhibitors are highly effective in killing nonreplicating Mycobacterium tuberculosis that is evaluated by using the Wayne low oxygen model. In addition, a series of drug resistant Mycobacterium spp. are sensitive to the MenA inhibitors. The results are expected to be of significance in terms of discovering new lead compounds that can be developed into new drugs to combat unmet diseases caused by Mycobacterium tuberculosis.

Methicillin-resistant Staphylococcus aureus (MRSA) is one of the most frequent nosocomial pathogens in developed countries. Although several novel antibacterial agents possessing novel mode of action have been developed to date, the continuous effort to investigate an effective combination of front-line drugs is considered important in anti-MRSA drug development. The combination chemotherapy with front-line drugs is expected to provide effective, safe, and less expensive treatment. Oral trimethoprim/sulfamethoxazole combination therapy has been utilized for treatment of several nosocomical infections. Importantly, no antagonism has been reported for combinations of trimethoprim with many other front-line antibiotics. MiddleBrook Pharmaceuticals has developed the pulsatile delivery systems of three to four different antibacterial agents, including trimethoprim and sulfamethoxazole, for the treatment of MRSA infections. The liberation of individual drugs theoretically follows a programmable lag phase (no re...

A wide variety of p-tolyl thioriboside donors are examined for O-ribosylations of primary and secondary alcohols. p-Tolylsulfenyl trifluoromethanesulfonate (p-TolSOTf) is very effective in promoting O-ribosylations with p-tolyl thioriboside; all reactions are completed within 1-15 min to provide the desired products in good yield with reliable alpha/beta selectivity. A wide range of functional groups are tolerated under these conditions. The described O-ribosylation conditions are very useful for the generation of ribosaminouridine library molecules in solution or on polymer support.

An acid- and base-stable protecting group for carboxylic acids is described. The esters of (2,6-dichloro-4-methoxyphenyl)(2,4-dichlorophenyl)methanol are stable to Bronsted and Lewis acids, Bronsted bases, and a wide variety of nucleophiles; however, the esters can be conveniently deprotected by a solvolytic displacement reaction with 20% trifluoroacetic acid.

An acid and base stable hydroxytetrachlorodiphenylmethyl (HTPM) linker is developed for polymer-supported organic synthesis. The linkers reported here are utilized for loading carboxylic acids, amines, alcohols, and phenols, and are stable to Brønsted and Lewis acids, Brønsted bases, and a wide variety of nucleophiles. However, the HTPM linkers can conveniently be cleaved by the solvolytic displacement reactions with 20% TFA. [structure: see text]

An efficient chemoenzymatic synthesis of UDP- N -acetylmuramyl- l -alanyl-γ- d -glutamyl- meso -diaminopimelyl- d -alanyl- d -alanine (Park’s nucleotide) is reported. UDP-MurNAc is efficiently synthesized by a minimum number of protecting strategies. One-pot amino acid ligation reactions catalyzed by MurC, D, E, and F enzymes are amenable to scale-up production.

Peptidoglycan (PG) is unique to bacteria, and thus, the enzymes responsible for its biosynthesis are promising antibacterial drug targets. The membrane-embedded enzymes in PG remain significant challenges in studying their mechanisms due to the fact that preparations of suitable enzymatic substrates require time-consuming biological transformations or chemical synthesis. Lipid I (MurNAc(pentapeptide)-pyrophosphoryl prenol) is an important PG biosynthesis intermediate to study the central enzymes, translocase I (MraY/MurX) and MurG. Lipid I isolated from nature contains the C_(50)- or C_(55)-prenyl unit that shows extremely poor water-solubility that renders studies of translocase I and MurG enzymes difficult. We have studied biological transformation of water soluble lipid I fluorescent probes using bacterial membrane fractions and purified MraY enzymes. In our investigation of the minimum structural requirements of the prenyl phosphates in MraY-catalyzed lipid I synthesis, we found that (2Z,6E)-farnesyl phosphate (C_(15)-phosphate) can be recognized by Escherichia coli MraY to generate the water-soluble lipid I fluorescent probe in high-yields. Under the optimized conditions, the same reaction was performed by using the purified MraY from Hydrogenivirga spp. to afford the lipid I analog with high-yields in a short reaction time.

A novel method for the preparation of oligopeptides with a PS-ammonium fluoride in the solution phase is reported. The synthesis of lipid II pentapeptide is efficiently synthesized via a PS-ammonium fluoride without chromatographic purifications. The method reported here is very convenient to synthesize a relatively large amount of oligopeptides with abundantly available Fmoc-protected amino acids in a time efficient manner.

Reliable N-alkylations of secondary amines have been developed. By using DIAD and TPP (or PS-TPP) a variety of secondary amines can be converted to the corresponding tertiary amines in good to excellent yields with diverse alkylhalides; no formation of quaternary amine salts are observed. These protocols are amenable to combinatorial chemistry libraries, and are also useful for the syntheses of secondary amines by an acid lysis of the cleavable tertiary amino resins.

An expeditious sialylation reaction with phenylthioglycoside 4 as a sialyl donor and MeSOTf as a promoter was developed. These conditions are very useful for synthesizing ganglioside GM3 (1), its C8‐ceramide analog 2, and 3‐deoxy analog 3 of 2 in an efficient manner. The GM3 analog 2, whose hydrophilicity is increased by shortening the ceramide moiety, exhibits increased growth inhibiton of KB cells. The 3‐hydoxy group of ceramide does not influence its activity against KB cells.

Indane-derived bis(oxazolines) were synthesized in two steps and 93% overall yield starting from commercially available substrates. This ligand is as effective as tert-butyl bis(oxazoline) in hetero Diels–Alder reaction both in solution and on polymer support.