Design and synthesis of C-aryl angular luotonins via a one-pot aza-Nazarov-Friedlander sequence and their Topo-I inhibition studies along with C-aryl vasicinones and luotonins.

A facile one-pot synthesis of C-ring substituted angular luotonins has been realized via a methanesulfonic acid mediated aza-Nazarov-Friedlander condensation sequence on quinazolinonyl enones. Topoisomerase I (topo-I) inhibition studies revealed that the angular luotonin library (7a-7l) and their regioisomeric analogs (linear luotonins, 8a-8l) are weak negative modulators, compared to camptothecin. These results would fare well for the design of topo-I-inert luotonins for non-oncological applications such as anti-fungal and insecticide lead developments. Surprisingly, the tricyclic vasicinones (9h, 9i, and 9j) showed better topo-I inhibition compared to pentacyclic C-aryl luotonins providing a novel pharmacophore for further explorations.

Total Synthesis of the Nagelamides - Synthetic Studies toward the Reported Structure of Nagelamide D and Nagelamide E Framework.

The nagelamides are a small subset of the oroidin family of marine sponge-derived alkaloids and are, for the most part, dimeric in nature. As part of our efforts to develop synthetic access to this family, a Stille cross-coupling strategy is used to construct the bis-imidazolyl core skeleton. Reduction of the bis-vinylimidazole delivered the core framework of nagelamide D. Introduction of the 2-amino groups via the corresponding azides and introduction of the pyrrolecarboxamides through a double Mitsunobu reaction using a pyrrole hydantoin provided the putative structure of nagelamide D. The spectroscopic data for the synthetic and sponge-derived materials did not match well, whereas the spectroscopic data were a good match for closely related oroidin alkaloids, supporting the structure of the synthetic material. The structure of the synthetic material was further corroborated by obtaining an X-ray crystal structure of a derivative. Electrocyclization of an advanced precursor affords a dihydrobenzimidazole, which is expected to serve as a key intermediate en route to nagelamide E and ageliferin.

Synthesis and biofilm inhibition studies of 2-(2-amino-6-arylpyrimidin-4-yl)quinazolin-4(3H)-ones.

Synthesis of novel 4(3H)-quinazolinonyl aminopyrimidine derivatives has been achieved via quinazolinonyl enones which in turn were obtained from 2-acyl-4(3H)-quinazolinone. They have been assayed for biofilm inhibition against Gram-positive (methicillin-resistant Staphylococcus aureus (MRSA)) and Gram-negative bacteria (Acinetobacter baumannii). The analogues with 2,4,6-trimethoxy phenyl, 4-methylthio phenyl, and 3-bromo phenyl substituents (5h, 5j & 5k) have been shown to inhibit biofilm formation efficiently in MRSA with IC50 values of 20.7-22.4 µM). The analogues 5h and 5j have demonstrated low toxicity in human cells in vitro and can be investigated further as leads.

Hydantoin-based molecular photoswitches.

A new family of molecular photoswitches based on arylidenehydantoins is described together with their synthesis and photochemical and photophysical studies. A series of hydantoin derivatives have been prepared as single isomers using simple and versatile chemistry in good yields. Our studies show that the photostationary states of these compounds can be easily controlled by means of external factors, such as the light source or filters. Moreover, the detailed investigations proved that these switches are efficient (i.e., they make efficient use of the light energy, are high fatigue resistant, and are very photostable). In some cases, the switches can be completely turned on/off, a desirable feature for specific applications. A series of theoretical calculations have also been carried out to understand the photoisomerization mechanism at the molecular level.

Diversity oriented total synthesis (DOTS) of pyridoquinazolinone alkaloids and their analogues.

A short diversity oriented total synthesis (DOTS) of substituted rutaecarpines, homo-luotonins, homo-vasicinone, homo-isaindigotones and homo-vasnetine has been achieved from the key tricyclic intermediate. The [6,6,6] tricyclic ketone, the mackinazolindione, was accessed from simple substrates i.e., quinazolinone diester obtained from the disubstituted anthranilamide which in turn was prepared from the coupling of amino acid ester and ethyl oxalyl chloride with isatoic anhydride and Dieckmann condensation chemistry.

Detour of prenostodione synthesis towards pyrazolones for antibacterial activity.

Our attempts to prepare indolyl acid (3), enroute to prenostodione (2), from phenyl-hydrazine following a reported procedure of Fischer-Indole synthesis rather lead to ethyl 2-(5-oxo-1-phenyl-2,5-dihydro-1H-pyrazol-3-yl)acetate as a major product, which underwent facile condensation with aldehydes to provide the pyrazolones. Intrigued by the opportunity for the diversity oriented synthesis of substituted pyrazolones, we have developed a facile one pot approach for pyrazolones and screened for antibacterial activity and, herein, results are reported.

Total syntheses of oroidin, hymenidin and clathrodin.

The total syntheses of oroidin, hymenidin and clathrodin are reported via the intermediacy of an imidazo[1,2-a]pyrimidine derivative. The chemistry described herein obviates the need for expensive guanidine reagents, multiply protected prefunctionalized 2-aminoimidazole synthons, or the need for laborious olefinations thereby achieving synthetic efficiency amenable to scale-up. The approach outlined in this manuscript provides an opportunity for further functionalizations through the imidazo[1,2-a]pyrimidine core and through functional groups placed strategically on the side chain.

The hydro-chloride salt of 4-hy-droxy-N,N-di-n-propyl-tryptamine (4-HO-DPT).

The title compound, 4-hy-droxy-N,N-di-n-propyl-tryptammonium (4-HO-DPT) chloride {systematic name: N-[2-(4-hy-droxy-1H-indol-3-yl)eth-yl]-N-propyl-propan-1-aminium chloride}, C16H25N2O+·Cl-, has a singly protonated trypt-ammonium cation and one chloride anion in the asymmetric unit. A series of N-H⋯Cl and O-H⋯Cl hydrogen bonds connect the ions together in ladder chains along [010].

Electrospinning of tyrosine-based oligopeptides: Self-assembly or forced assembly?

Short oligomeric peptides typically do not exhibit the entanglements required for the formation of nanofibers via electrospinning. In this study, the synthesis of nanofibers composed of tyrosine-based dipeptides via electrospinning, has been demonstrated. The morphology, mechanical stiffness, biocompatibility, and stability under physiological conditions of such biodegradable nanofibers were characterized. The electrospun peptide nanofibers have diameters less than 100 nm and high mechanical stiffness. Raman and infrared signatures of the peptide nanofibers indicate that the electrostatic forces and solvents used in the electrospinning process lead to secondary structures different from self-assembled nanostructures composed of similar peptides. Crosslinking of the dipeptide nanofibers using 1,6-diisohexanecyanate (HMDI) improved the physiological stability, and initial biocompatibility testing with human and rat neural cell lines indicate no cytotoxicity. Such electrospun peptides open up a realm of biomaterials design with specific biochemical compositions for potential biomedical applications such as tissue repair, drug delivery, and coatings for implants.

Synthesis of C-Ring-Substituted Vasicinones and Luotonins via Regioselective Aza-Nazarov Cyclization of Quinazolinonyl Enones.

A facile synthesis of C-ring substituted luotonins and vasicinones has been realized via a super-acid-mediated aza-Nazarov cyclization of quinazolinonyl enones. The regioselectivity of the cyclization is highly dependent on proton availability in the reaction medium.

Studies toward total synthesis of divergolides C and D.

A facile synthesis of the western segment of divergolides C and D has been developed. Exploratory studies with two disconnections, i.e., C4-C5 vs C5-C6, for elaboration of the ansa bridge to the sterically demanding hexasubstituted naphthalenic aromatic core using a chiral synthon assembled from D-glucose via a stereoselective Johnson orthoester rearrangement is described. The studies set the stage for the completion of the total synthesis of the biologically important novel ansamycins, divergolides C and D, and their structural congeners.