Vunnam Srinivasulu

Water mediated Heck and Ullmann couplings by supported palladium nanoparticles: importance of surface polarity of the carbon spheres

Heterogeneous palladium nanoparticle catalysts that are supported on amphiphilic carbon spheres (Pd@CSP) have been utilized for water-mediated Heck coupling reactions of aryl halides with different alkenes under phosphine free as well as aerobic conditions. Furthermore, a variety of Heck coupling reactions using different bases and solvents, including organic polar and non-polar solvents, have been explored. Aryl bromides are also well activated in Heck coupling reactions in organic polar solvent and as well as in water. In addition, Ullmann coupling reactions of aryl iodides have been catalyzed in water with the aid of phase transfer catalysts (PTC) in moderate yields. A plausible mechanism for the catalytic activity of Pd@CSP in the case of the Ullmann reaction is also established. It has been demonstrated that the hydrophobic effects of the catalyst surface play an important role in catalyst activity in water. In addition, the E-factor analysis verified that our present protocol is significantly comparable with other catalytic systems and explains the improved greenness. Moreover, the catalyst described in this process is not only greener, but also retains its significant activity for up to four catalytic cycles for the Heck coupling reactions. The surface polarity of the amphiphilic carbon spheres results in higher activity under these conditions.

Design and Synthesis of C3-Pyrazole/Chalcone-Linked Beta-Carboline Hybrids: Antitopoisomerase I, DNA-Interactive, and Apoptosis-Inducing Anticancer Agents

A series of β‐carboline hybrids bearing a substituted phenyl and a chalcone/(N‐acetyl)‐pyrazole moiety at the C1 and C3 positions, respectively, was designed, synthesized, and evaluated for anticancer activity. These new hybrid molecules showed significant cytotoxic activity, with IC50 values ranging from <2.0 μM to 80 μM, and the structure–activity relationships (SAR) associated with substitutions at positions 1 and 3 of these hybrids was clearly addressed. Further, induction of apoptosis was confirmed by Annexin V‐FITC, Hoechst staining, and DNA fragmentation analysis. In addition, DNA photocleavage studies proved that two of the hybrids, (E)‐1‐(furan‐2‐yl)‐3‐(1‐(4‐(trifluoromethyl)phenyl)‐9H‐pyrido[3,4‐b]indol‐3‐yl)prop‐2‐en‐1‐one (7 d) and 1‐(3‐(furan‐2‐yl)‐5‐(1‐(4‐(trifluoromethyl)phenyl)‐9H‐pyrido[3,4‐b]indol‐3‐yl)‐4,5‐dihydro‐1H‐pyrazol‐1‐yl)ethanone (8 d) could effectively cleave pBR322 plasmid DNA upon irradiation with UV light. Active hybrid 8 d inhibited DNA topoisomerase I activity efficiently and preserved DNA in the supercoiled form. To further corroborate the biological activities, as well as to understand the nature of the interaction of these hybrids with DNA, spectroscopic studies were also performed. Unlike simple β‐carboline alkaloids, the binding mode of these new hybrid molecules with DNA was not similar, and both biophysical as well as molecular docking studies speculated a combilexin‐type of interaction with DNA. Further, an in silico study of these β‐carboline hybrids revealed their drug‐like properties.

DNA-binding affinity and anticancer activity of β-carboline–chalcone conjugates as potential DNA intercalators: Molecular modelling and synthesis

A new series of DNA-interactive β-carboline-chalcone conjugates have been synthesized and evaluated for their in vitro cytotoxicity and DNA-binding affinity. It has been observed that most of these new hybrids have shown potent cytotoxic activities on A-549 (lung adenocarcinoma) cell lines with IC50 values lower than 10 μM. The hybrid 7b is more effective against some of the selected cancer cell lines with IC50 values less than 50 μM. In addition, compounds 7e, 7k, 7p-u has displayed significant elevation in ΔTm of DNA in comparison to Adriamycin, suggesting significant interaction and remarkable DNA stabilization. The DNA intercalation of these new hybrids has been investigated by fluorescence titration, DNA viscosity measurements, molecular docking as well as molecular dynamics and the results are in agreement with the thermal denaturation studies.

Design and synthesis of dithiocarbamate linked β-carboline derivatives: DNA topoisomerase II inhibition with DNA binding and apoptosis inducing ability.

A series of new β-carboline-dithiocarbamate derivatives bearing phenyl, dithiocarbamate and H/methyl substitutions at position-1, 3 and 9, respectively, were designed and synthesized. These derivatives 8a-l and 13a-l and their starting precursors (7 a-d and 12 a-d) have been evaluated for their in vitro cytotoxic activity on selected human cancer cell lines. Among the derivatives tested, 7 c, 12 c, 8 a, 8 d, 8 i, 8 j, 8 k, 8l and 13 d-l exhibited considerable cytotoxicity against most of the tested cancer cell lines (IC50<10μM). Interestingly, most of the derivatives (8 a-l and 13a-l) exhibited enhanced activity than their precursors (7 a-d and 12 a-d), which indicates that the combination of dithiocarbamate with β-carboline enhances the cytotoxicity of 8 a-l and 13 a-l. Moreover, the derivatives 8 j and 13 g exhibited significant cytotoxic activity with IC50 values of 1.34 μM and 0.79 μM on DU-145 cancer cells, respectively. Further, the induction of apoptosis by these derivatives was confirmed by Annexin V-FITC and Hoechst staining assays. However, both biophysical as well as molecular docking studies suggested a combilexin-type of interaction between these derivatives and DNA, unlike simple β-carbolines. With a view to understand their mechanism of action, DNA topoisomerase II (topo II) inhibition assay was also performed. Overall, the present study emphasizes the importance of linking a dithiocarbamate moiety to the β-carboline scaffold for exhibiting profound activity.

Synthesis and Biological Evaluation of Benzo[b]furans as Inhibitors of Tubulin Polymerization and Inducers of Apoptosis

A series of benzo[b]furans was synthesized with modification at the 5‐position of the benzene ring by introducing C‐linked substituents (aryl, alkenyl, alkynyl, etc.). These compounds were evaluated for their antiproliferative activities, inhibition of tubulin polymerization, and cell‐cycle effects. Some compounds in this series displayed excellent activity in the nanomolar range against lung cancer (A549) and renal cell carcinoma (ACHN) cancer cell lines. (6‐Methoxy‐5‐((4‐methoxyphenyl)ethynyl)‐3‐methylbenzofuran‐2‐yl)(3,4,5‐trimethoxyphenyl)methanone (26) and (E)‐3‐(6‐methoxy‐3‐methyl‐2‐(1‐(3,4,5‐trimethoxyphenyl)vinyl)benzofuran‐5‐yl)prop‐2‐en‐1‐ol (36) showed significant activity in the A549 cell line, with IC50 values of 0.08 and 0.06 μM, respectively. G2/M cell‐cycle arrest and subsequent apoptosis was observed in the A549 cell line after treatment with these compounds. The most active compound in this series, 36, also inhibited tubulin polymerization with a value similar to that of combretastatin A‐4 (1.95 and 1.86 μM, respectively). Furthermore, detailed biological studies such as Hoechst 33258 staining, DNA fragmentation and caspase‐3 assays, and western blot analyses with the pro‐apoptotic protein Bax and the anti‐apoptotic protein Bcl‐2 also suggested that these compounds induce cell death by apoptosis. Molecular docking studies indicated that compound 36 interacts and binds efficiently with the tubulin protein.

Synthesis and biological evaluation of 4-aza-2,3-dihydropyridophenanthrolines as tubulin polymerization inhibitors

A series of novel 4-aza-2,3-dihydropyridophenanthrolines 12(a-t) were synthesized by a one-step three component condensation of 1,10-phenanthroline amine, tetronic acid and various aromatic aldehydes. These were evaluated for their antiproliferative activity against three human cancer cell lines (MIAPACA, MCF-7 and HeLa) using SRB assay. Majority of the tested compounds exhibited significant anticancer activity on these cell lines and interestingly compounds 12h and 12i were more potent than etoposide and podophyllotoxin against all three tested cancer cell lines with GI50 values in the range of 0.01-0.5 μM. Furthermore, these compounds showed significant inhibition of tubulin polymerization which is comparable to that of podophyllotoxin and disrupted microtubule network by accumulating tubulin in the soluble fraction. The flow cytometry analysis confirmed that the synthesized compounds led to cell cycle arrest at the G2/M phase. Moreover, the structure activity relationship studies in this series are also discussed.

Synthesis of 2-aryl-1,2,4-oxadiazolo-benzimidazoles: Tubulin polymerization inhibitors and apoptosis inducing agents

A new series of 2-aryl 1,2,4-oxadiazolo-benzimidazole conjugates have been synthesized and evaluated for their antiproliferative activity in the sixty cancer cell line panel of the National Cancer Institute (NCI). Compounds 5l (NSC: 761109/1) and 5x (NSC: 761814/1) exhibited remarkable cytotoxic activity against most of the cancer cell lines in the one dose assay and were further screened at five dose concentrations (0.01, 0.1, 1, 10 and 100 μM) which showed GI50 values in the range of 0.79-28.2 μM. Flow cytometric data of these compounds showed increased cells in G2/M phase, which is suggestive of G2/M cell cycle arrest. Further, compounds 5l and 5x showed inhibition of tubulin polymerization and disruption of the formation of microtubules. These compounds induce apoptosis by DNA fragmentation and chromatin condensation as well as by mitochondrial membrane depolarization. In addition, structure activity relationship studies within the series are also discussed. Molecular docking studies of compounds 5l and 5x into the colchicine-binding site of the tubulin, revealed the possible mode of interaction by these compounds.

A one-pot azido reductive tandem mono-N-alkylation employing dialkylboron triflates: online ESI-MS mechanistic investigation.

An efficient one-pot reductive tandem mono-N-alkylation of both aromatic and aliphatic azides using dialkylboron triflates as alkylating agents has been examined under standardized reaction conditions. This methodology after optimization has been employed toward the syntheses of various secondary alkyl as well as aryl amines, including the synthesis of N10-butylated pyrrolo[2,1-c][1,4]benzodiazepine-5,11-diones via in situ azido reductive-cyclization process. This protocol is particularly attractive to provide an environmentally benign and practical method for mono-N-alkylation from organic azides without the use of toxic catalysts or corrosive alkylating agents. In addition, the mechanistic aspects have been investigated and the intermediates associated with this selective transformation have been intercepted and characterized by online monitoring of the reaction by ESI-MS/MS.

Dithiocarbamate/piperazine bridged pyrrolobenzodiazepines as DNA-minor groove binders: Synthesis, DNA-binding affinity and cytotoxic activity

A new series of C8-linked dithiocarbamate/piperazine bridged pyrrolo[2,1-c][1,4]benzodiazepine conjugates (5a-c, 6a,b) have been synthesized and evaluated for their cytotoxic potential and DNA-binding ability. The representative conjugates 5a and 5b have been screened for their cytotoxicity against a panel of 60 human cancer cell lines. Compound 5a has shown promising cytotoxic activity on selected cancer cell lines that display melanoma, leukemia, CNS, ovarian, breast and renal cancer phenotypes. The consequence of further replacement of the 3-cyano-3,3-diphenylpropyl 1-piperazinecarbodithioate in 5b and 5c with 4-methylpiperazine-1-carbodithioate yielded new conjugates 6a and 6b respectively. In addition, the compounds 5c and 6a,b have been evaluated for their in vitro cytotoxicity on some of the selected human cancer cell lines and these conjugates have exhibited significant cytotoxic activity. Further, the DNA-binding ability of these new conjugates has been evaluated by using thermal denaturation (ΔTm) studies. The correlation between structure and DNA-binding ability has been investigated by molecular modeling studies which predicted that 6b exhibits superior DNA-binding ability and these are in agreement with the experimental DNA-binding studies.

2-aryl benzimidazole conjugate induced apoptosis in human breast cancer MCF-7 cells through caspase independent pathway

Apoptosis is a representative form of programmed cell death, which has been assumed to be critical for cancer prevention. Thus, any agent that can induce apoptosis may be useful for cancer treatment and apoptosis induction is arguably the most potent defense against cancer promotion. In our previous studies, 2-aryl benzimidazole conjugates were synthesized and evaluated for their antiproliferative activity and one of the new molecule (2f) was considered as a potential lead. This lead molecule showed significant antiproliferative activity against human breast cancer cell line, MCF-7. The results of the present study revealed that this compound arrested the cell cycle at G2/M phase. Topoisomerase II inhibition assay and Western blot analysis suggested that this compound effectively inhibits topoisomerase II activity which leads to apoptotic cell death. Apoptosis induction in MCF-7 cells was further confirmed by loss of mitochondrial membrane potential (∆Ψm), release of cytochrome c from mitochondria, an increase in the level of apoptosis inducing factor (AIF), generation of reactive oxygen species (ROS), up regulation of proapoptotic protein Bax and down regulation of anti apoptotic protein Bcl-2. Apoptosis assay using Annexin V-FITC assay also suggested that this compound induced cell death by apoptosis. However, compound 2f induced apoptosis could not be reversed by Z-VAD-FMK (a pan-caspase inhibitor) demonstrated that the 2f induced apoptosis was caspase independent. Further, 2f treatment did not activate caspase-7 and caspase-9 activity, suggesting that this compound induced apoptosis in breast cancer cells via a caspase independent pathway. Most importantly, this compound was less toxic towards non-tumorigenic breast epithelial cells, MCF-10A. Furthermore, docking studies also support the potentiality of this molecule to bind to the DNA topoisomerase II.Graphical Abstract