Barnali Maiti

Traceless synthesis of hydantoin fused tetrahydro-beta-carboline on ionic liquid support in green media.

A novel ionic liquid (IL) supported, green synthetic protocol has been developed toward the synthesis of oxo and thio hydantoin analogues tethered with tetrahydro-beta-carboline by the use of focused microwave irradiation. IL-bound tryptophan underwent a Pictet-Spengler reaction with various carbonyl compounds to generate the IL-immobilized tetrahydro-beta-carbolines in aqueous isopropanol media. Subsequent reaction of substituted tetrahydro-beta-carboline derivatives with various isocyanates and isothiocyanate provided a three-dimensional combinatorial library in a traceless fashion.

Multicomponent solvent-free synthesis of benzimidazolyl imidazo[1,2-a]-pyridine under microwave irradiation.

A novel one-pot, three-component reaction employing variously substituted benzimidazole-linked amino pyridines, aldehydes, and isonitriles catalyzed by scandium(III) triflate under solvent-free conditions were accomplished. This new synthetic methodology facilitates the rapid generation of intricate molecular frameworks in three-dimensional fashion leading to benzimidazole-imidazo[1,2-a] pyridines. This approach is envisioned as an environmentally benign process and a simple operation to the biological interesting compounds. The present synthetic sequence permits the introduction of three points of structural diversity to expand chemical space with high purity and excellent yields.

Application of Pictet–Spengler Reaction to Indole-Based Alkaloids Containing Tetrahydro-β-carboline Scaffold in Combinatorial Chemistry

Indole-based alkaloids are well-known in the literature for their diverse biological properties. Polysubstituted optically active tetrahydro-β-carboline derivatives functionalized on C-1 position are the common structural motif in most of the indole-based alkaloids, as well as highly marketed drugs. The stereoselective Pictet-Spengler reaction is one of the currently most important synthetic techniques used for the preparation of these privileged tetrahydro-β-carboline scaffolds. To date, there are numerous research reports that have been published on the synthesis of the tetrahydro-β-carboline scaffold both on solid phase, as well as in solution phase. Moreover rapid growth has been observed for the enantioselective synthesis of tetrahydro-β-carboline scaffold using chiral organocatalysts. In this Review, efforts have been taken to shed light on the latest information available on different strategies to synthesize tetrahydro-β-carboline both on solid phase and in solution phase during the last 20 years. Furthermore, we believe that the present synthetic methodologies covered in this Review will help to improve the status of this privileged tetrahydro-β-carboline scaffold in its use for drug discovery.

Microwave-Assisted Linear Approach Toward Highly Substituted Benzo[d]oxazol-5-yl-1H-benzo[d]imidazole on Ionic Liquid Support

A novel and efficient diversity-oriented synthetic approach was employed to access the benzo[d]oxazol-5-yl-1H-benzo[d]imidazole on ionic liquid support, which helps to absorb microwave irradiation. In this paper, we successfully coupled 4-hydroxy-3-nitrobenzoic acid onto ionic liquid-immobilized o-phenylenediamine, which subsequently underwent an acid mediated, ring closure reaction leading to benzimidazole derivatives. After hydrogenation of the nitro group to an amine, the resulting ionic liquid conjugate was reacted with 1,1-thiocarbonyldiimidazols to yield an ionic liquid tagged-benzoxazol. Final skeletal diversity of the present scaffold was further achieved by S-alkylation with alkyl and aryl bromides. The benzo[d]oxazol-5-yl-1H-benzo[d]imidazole was finally cleaved smoothly from the ionic liquid support with sodium methoxide in methanol under microwave irradiation. This methodology has provided access to a small, diverse library by straightforward and simple operations and could be applied readily in various drug discovery programs.

Andrographolide downregulates the v-Src and Bcr-Abl oncoproteins and induces Hsp90 cleavage in the ROS-dependent suppression of cancer malignancy

Andrographolide is a diterpenoid compound isolated from Andrographis paniculata that exhibits anticancer activity. We previously reported that andrographolide suppressed v-Src-mediated cellular transformation by promoting the degradation of Src. In the present study, we demonstrated the involvement of Hsp90 in the andrographolide-mediated inhibition of Src oncogenic activity. Using a proteomics approach, a cleavage fragment of Hsp90α was identified in andrographolide-treated cells. The concentration- and time-dependent induction of Hsp90 cleavage that accompanied the reduction in Src was validated in RK3E cells transformed with either v-Src or a human truncated c-Src variant and treated with andrographolide. In cancer cells, the induction of Hsp90 cleavage by andrographolide and its structural derivatives correlated well with decreased Src levels, the suppression of transformation, and the induction of apoptosis. Moreover, the andrographolide-induced Hsp90 cleavage, Src degradation, inhibition of transformation, and induction of apoptosis were abolished by a ROS inhibitor, N-acetyl-cysteine. Notably, Hsp90 cleavage, decreased levels of Bcr-Abl (another known Hsp90 client protein), and the induction of apoptosis were also observed in human K562 leukemia cells treated with andrographolide or its active derivatives. Together, we demonstrated a novel mechanism by which andrographolide suppressed cancer malignancy that involved inhibiting Hsp90 function and reducing the levels of Hsp90 client proteins. Our results broaden the molecular basis of andrographolide-mediated anticancer activity.

Microwave Controlled Reductive Cyclization: A Selective Synthesis of Novel Benzimidazole-alkyloxypyrrolo[1,2-a]quinoxalinones

An efficient cascade synthesis of novel benzimidazole linked alkyloxypyrrolo[1,2-a]quinoxalinones was explored on soluble polymer support under microwave irradiation. Two exclusive protocols have been developed for the partial and full reductive cyclization by controlling the microwave energy. Commencing from the same substrate, ortho nitro pyrrol carboxylates, N-hydroxy pyrroloquinoxalinones were obtained by partial reductive cyclization (60 °C, 7 min), and the synthesis of pyrroloquinoxalinones was accomplished by full reductive cyclization (85 °C, 12 min). This method represents the first synthesis of N-hydroxy pyrroloquinoxalinones using Pd/C and ammonium formate as reducing agents. Further employing a variety of alkyl bromides, the obtained pyrroloquinoxalinones were transformed to their corresponding O- and N-alkylated analogues to deliver the diversified, novel molecular entities.

Polymer supported synthesis of novel benzoxazole linked benzimidazoles under microwave conditions: In vitro evaluation of VEGFR-3 kinase inhibition activity

An efficient soluble polymer-supported method has been developed for the parallel synthesis of substituted benzimidazole linked benzoxazoles using focused microwave irradiation. The key step involves the amidation of 4-hydroxy-3-nitrobenzoic acid with polymer-immobilized o-phenylenediamine. Application of mild acidic conditions promoted the ring closure to furnish the benzimidazole ring. After hydrogenation of the nitro-group to amine, the resulted polymer conjugates underwent efficient ring closure with various alkyl, aryl and heteroaryl isothiocyanates to generate the polymer-bound benzimidazolyl benzoxazoles. The polymer-bound compounds were finally cleaved from the support to furnish benzimidazole linked benzoxazole derivatives. The efficacy of the resultant angular bis-heterocyclic library was studied against vascular endothelial growth factor receptor (VEGFR-3). The preliminary screening of these novel compounds exhibits moderate to high inhibition (IC(50) = 0.56-1.42 μM). This protocol provides an easy access to novel angular bis-heterocycles which have potential for the discovery of novel leads for targeted cancer therapeutics.