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A concise total synthesis of (±)-pestalachloride C and (±)-pestalachloride D was achieved through a Knoevenagel/hetero-Diels-Alder cascade reaction to test the nonenzymatic biosynthetic hypothesis of Shao, Wang, and co-workers. The cascade reaction generates a mixture of racemic indano[2,1- c]chromans like those found in the natural products.

Four phthalazinones (CIDs 22334057, 22333974, 22334032, 22334012) and one isoquinolone (CID 5224943) were previously shown to be potent enhancers of antifungal activity of fluconazole against Candida albicans. Several even more potent analogues of these compounds were identified, some with EC50 as low as 1 nM, against C. albicans. The compounds exhibited pharmacological synergy (FIC < 0.5) with fluconazole. The compounds were also shown to enhance the antifungal activity of isavuconazole, a recently FDA approved azole antifungal. Isoquinolone 15 and phthalazinone 24 were shown to be active against several resistant clinical isolates of C. albicans.

A spiroindolinone, (1S,3R,3aR,6aS)-1-benzyl-6'-chloro-5-(4-fluorophenyl)-7'-methylspiro[1,2,3a,6a-tetrahydropyrrolo[3,4-c]pyrrole-3,3'-1H-indole]-2',4,6-trione, was previously reported to enhance the antifungal effect of fluconazole against Candida albicans. A diastereomer of this compound was synthesized, along with various analogues. Many of the compounds were shown to enhance the antifungal effect of fluconazole against C. albicans, some with exquisite potency. One spirocyclic piperazine derivative, which we have named synazo-1, was found to enhance the effect of fluconazole with an EC50 value of 300 pM against a susceptible strain of C. albicans and going as low as 2 nM against some resistant strains. Synazo-1 exhibits true synergy with fluconazole, with an FIC index below 0.5 in the strains tested. Synazo-1 exhibited low toxicity in mammalian cells relative to the concentrations required for antifungal synergy.

Cysteine-rich peptides are valued as tags for biarsenical fluorophores and as environmentally important reagents for binding toxic heavy metals. Due to the inherent difficulties created by cysteine, the power of one-bead one-compound (OBOC) libraries has never been applied to the discovery of short cysteine-rich peptides. We have developed the first method for the synthesis, screening, and sequencing of cysteine-rich OBOC peptide libraries. First, we synthesized a heavily biased cysteine-rich OBOC library, incorporating 50% cysteine at each position (Ac-X8-KM-TentaGel). Then, we developed conditions for cysteine alkylation, cyanogen bromide cleavage, and direct MS/MS sequencing of that library at the single bead level. The sequencing efficiency of this library was comparable to a traditional cysteine-free library. To validate screening of cysteine-rich OBOC libraries, we reacted a library with the biarsenical FlAsH and identified beads bearing the known biarsenical-binding motif (CCXXCC). These results enable OBOC libraries to be used in high-throughput discovery of cysteine-rich peptides for protein tagging, environmental remediation of metal contaminants, or cysteine-rich pharmaceuticals.

The antibiotic AT2433-B1 belongs to a therapeutically important class of antitumor agents. This natural product contains an indolocarbazole aglycone connected to a unique disaccharide consisting of a methoxyglucose and an amino sugar subunit, 2,4-dideoxy-4-methylamino-l-xylose. The configuration of the amino sugar distinguishes AT2433-B1 from its diastereoisomer iso-AT2433-B1. Here we have investigated the interaction of these two disaccharide indolocarbazole derivatives with different DNA sequences by means of DNase I footprinting and surface plasmon resonance (SPR). Accurate binding measurements performed at 4 and 25°C using the BIAcore SPR method revealed that AT2433-B1 binds considerably more tightly to a hairpin oligomer containing a [CG]4 block than to an oligomer with a central [AT]4 tract. The kinetic analysis shows that the antibiotic dissociates much more slowly from the GC sequence compared to the AT one. Preferential binding of AT2433-B1 to GC-rich sequences in DNA was independently confirmed by DNase I footprinting experiments performed with a 117 bp DNA restriction fragment. The specific binding sequence 5′-AACGCCAG identified from the footprints was then converted into a biotin-labeled DNA hairpin duplex and compound interactions with this specific sequence were characterized by high resolution BIAcore SPR experiments. Such a combined approach provided a detailed understanding of the molecular basis of DNA recognition. The discovery that the glycosyl antibiotic AT2433-B1 preferentially recognizes defined sequences offers novel opportunities for the future design of sequence-specific DNA-reading small molecules.

The binding of madindoline A (Mad A) to gp130 is specific and noncovalent and displays a relatively low affinity. It is shown that the tricyclic 3a-hydroxytetrahydrofuro[2,3-b]indole (HFI) moiety of MadA alone is not sufficient for binding.

A library of over half a million octapeptides is synthesized and is exposed to light and air in pH 7.4 buffer to identify fluorogenic peptides that evolve under mild oxidative conditions. The study confirms that peptide fluorogenesis is dependent on sequence and not merely on the presence of tryptophan.

Research has been conducted on alpha-silyl thioethers. The hypothesis that these thioethers could be converted to E-styrenes and then used for the synthesis of 3-hydroxybakuchiol and corylifolin has been tested and the details are reported.

Research has been conducted on the synthesis of the tryptophan-rich peptides. A path from ditryptophan-containing peptides to homofascaplysin C and indolo[2,3-alpha]carbazole has been created to cyclize N-acyliminium ions onto the biindole nucleus.

Indolocarbazole glycosides are unique for having two basic conformations. These include an 'open' conformation where the indolocarbazole NH is hydrogen bonded to the solvent and a 'closed' conformational design where a cyclic hydrogen bond exists between the indolocarbazone NH and the pyranose oxygen. The open conformation does not exhibit a commanding advantage, even in DMSO experiments, while the cyclic conformation becomes predominant in nonpolar environments.

The dimerization of tryptophan derivatives was shown to produce diastereomers with the same relative indoline stereochemistry. Also, the coupling constants in the N-tosyltryptophan dimers were found to be in agreement with a trans indoline stereochemistry. Therefore, a consistent model of the intramolecular trifluoroacetic acid-promoted dimerization of 3-alkylindoles, including tryptophan, has emerged.

The use of palladium-catalyzed ionizations in the synthesis of allosamizoline and mannostatin A is discussed. All reactions are conducted under an atmosphere of dry nitrogen. The reactions are analyzed by means of infrared spectra, high-resolution mass spectra and low-resolution mass spectra. Results indicate that palladium-catalyzed ionizations are highly capable of producing glycosidase inhibitors that speed up the synthesis of allosamizoline and mannostatin A.

The palladium-catalyzed enantiodifferentiation, resulting from specific ionization of cis-2-cycloalkene-1,4 diols substrate, also incorporates ligands based on 2-(diphenylphosphino)benzoic acid. Gradual, step-by-step changes in ligand structure enable the study of asymmetric induction possibilities. The ligand chirality determines the product stereochemistry in a regular manner that can be predicted using a mnemonic.

A study was conducted to explore the competition between carbene insertion and other processes like carbopalladation and [beta]-hydride elimination in the context of a palladium-catalyzed indane formation reaction. The palladium was shown to catalyze the insertion of trimethylsilylmethylene into aryl halides, leading to benzylpalladium intermediates that cyclize to give indenylsilanes through carbopalladation of pendant alkenes or allenes.

Research has been conducted on tert-butoxycarbonyl azide and allyl sulfides. The authors report that the iron(II)-catalyzed Bach reaction of these compounds has been extended in order to include propargyl sulfides and to produce N-allenylsulfenimides.

A study was conducted on stereoselective and enantioselective [2,3]-sigmatropic rearrangements of allylsulfonium ylides. The findings indicate that thia-Sommelet dearomatization may be performed by deprotonation with lithium diisopropylamide at low temperature resulting in the formation of hexatrienes containing quaternary stereogenic centers in excellent yields. Moreover, cyclic sulfonium ylides provide excellent diastereocontrol.

A new approach for the construction of highly fluorescent chromophores is described. It involves the initial acid-promoted delta1,delta1' dimerization of tryptophan-containing peptides, followed by oxidation, to produce heterodetic cyclic peptides. The dimerization products are treated with DDQ to induce the dehydrogenation of the indole ring, resulting to the removal of the stereogenic centers. Remaining in the solution is a fully aromatic delta1,delta1'-ditryptophan in high yield.

Constant stirring of indole-3-acetic acid methyl ester at room temperature results in the formation of 2,2'-indolyindoline (2) in 91% yield. Reaction of 2 with D-glucose in refluxing alcohol results in the formation of glycosylated derivatives. The presence of indole N-H resonance at delta 9.0-9.6 in the proton NMR of the glycosidic substrate indicates that glycosylation occurs on indoline.