Design, synthesis, and biological evaluation of novel 2,3-Di-O-Aryl/Alkyl sulfonate derivatives of l-ascorbic acid: Efficient access to novel anticancer agents via in vitro screening, tubulin polymerization inhibition, molecular docking study and ADME predictions.

A series of novel l-ascorbic acid derivatives bearing aryl and alkyl sulfonate substituents were synthesized and characterized. In vitro anticancer evaluation against MCF-7 (breast) and A-549 (lung) cancer cell lines revealed potent activity for most of the compounds, with 2b being equipotent to the standard drug colchicine against MCF-7 (IC50 = 0.04 µM). Notably, compound 2b displayed 89-fold selectivity for MCF-7 breast cancer over MCF-10A normal breast cells. Derivatives with two sulfonate groups (2a-g, 3a-g) exhibited superior potency over those with one sulfonate (4a-c,5g, 6b). Compounds 2b and 2c potently inhibited tubulin polymerization in A-549 cancer cells (73.12 % and 62.09 % inhibition, respectively), substantiating their anticancer potential through microtubule disruption. Molecular docking studies showed higher binding scores and affinities for these compounds at the colchicine-binding site of α, ß-tubulin compared to colchicine itself. In-silico ADMET predictions indicated favourable drug-like properties, with 2b exhibiting the highest binding affinity. These sulfonate derivatives of l-ascorbic acid represents promising lead scaffolds for anticancer drug development.

Design, synthesis, and biological evaluation of novel quinoline derivatives as small molecule mutant EGFR inhibitors targeting resistance in NSCLC: In vitro screening and ADME predictions.

Here in, we report the design, synthesis and in vitro anticancer activity of a novel series of 24 quinoline analogues of substituted amide and sulphonamide derivatives. The anticancer activity of the synthesised compounds was evaluated against the HCC827, H1975 (L858R/T790 M), A549 (WT EGFR), A-549 and BEAS-2B cell lines. The majority of quinoline compounds demonstrated a significant cytotoxic effect. Compound 21 was found to be the most potent, with IC50 values of 0.010 µM, 0.21 µM, 0.99 µM and 2.99 µM as compared to Osimertinib with IC50 values with of 0.0042 µM, 0.04 µM, 0.92 µM and 2.67 µM. Compound 21 exhibited promising inhibitory enzymatic activity against the EGFR L858R/T790 M with IC50 value of 138 nM, comparable to Osimertinib's 110 nM. Employing a Western blot assay on the phosphorylation of EGFR and the signalling pathways transmission in HCC827 cells, the anticancer activity of the synthesised compounds 18 and 21 was evaluated in terms of its mechanism of action. All the compounds were subjected to a comparative molecular docking study against various EGFR enzyme types, including the wild-type (PDB: 4I23) and T790 M mutant (PDB: 2JIV) enzymes. Furthermore, compounds were examined at the allosteric binding site of the EGFR enzyme with the L858R/T790 M/C797S mutation (PDB ID: 5D41). The MD simulation study was also performed for EGFR-compound 21 complex which indicates the stability compound 21 in both ATP and allosteric site of enzyme. Further, in silico ADME prediction studies of all derivatives were found promising, signifying the drug like properties.

Design and synthesis of novel conformationally constrained 7,12-dihydrodibenzo[b,h][1,6] naphthyridine and 7H-Chromeno[3,2-c] quinoline derivatives as topoisomerase I inhibitors: In vitro screening, molecular docking and ADME predictions.

Novel non-camptothecin (non-CPT) class of conformationally constrained, hitherto unknown 7,12-dihydrodibenzo[b,h][1,6] naphthyridine and 7H-Chromeno[3,2-c] quinoline derivatives have been designed, synthesized and evaluated for anti-cancer activity. In vitro anti-proliferation evaluation against human cancer cell lines (A549 and MCF-7) exhibited significant cytotoxicity. Among the derivatives (8-24), 8 (IC50 0.44 µM and IC50 0.62 µM) and 12 (IC50 0.69 µM and IC50 0.54 µM) were identified as the most promising candidate against A-549 and MCF-7 cancer cell lines respectively. Topo I inhibitory activity of 8 and 12 suggested that, they may be developed as potential anti-cancer molecules in future and rationalized by docking analysis with effective binding modes. Further, in silico ADME prediction studies of all derivatives were found promising, signifying the drug like properties. In precise, the present investigation displays a new strategy to synthesize and emphasis on anticancer activities of conformationally constrained dibenzo[b,h][1,6] naphthyridine derivatives and Chromeno[3,2-c] quinoline derivatives in the context of cancer drug development and refinement.

N-Benzylation of 6-aminoflavone by reductive amination and efficient access to some novel anticancer agents via topoisomerase II inhibition.

Series of novel N-benzyl derivatives of 6-aminoflavone (9a-n) were synthesized and evaluated for anticancer and topoisomerase II enzyme inhibition activity. All the synthesized compounds were screened for in vitro anticancer activity against human breast cancer cell line (MCF-7) and human lung cancer cell line (A-549). Among the synthesized compounds, 9f and 9g were found to be the most potent anticancer agents against human breast cancer cell line (MCF-7) with IC50 values of 9.35 µM and 9.58 µM, respectively. Compounds 9b, 9c and 9n exhibited promising anticancer activity against human lung cancer cell line (A-549) with 43.71%, 46.48% and 44.26% inhibition at the highest concentration of 10 µM, respectively. Compounds 9c, 9f and 9g have ability to inhibit the topoisomerase II enzyme. Compound 9f showed most potent topoisomerase II enzyme inhibition activity with IC50 value of 12.11 µM. Further, these compounds have a high potential to be developed as a promising topoisomerase II inhibitors.

Efficient and Green Synthesis of Bis(indolyl)Methanes using Thiamine Hydrochloride as an Organocatalyst: A Parallel Scrutiny of Microwave Irradiation versus Ultrasonicator Heating in Water.

Thiamine hydrochloride is reported to be a highly competent promoter for the synthesis of bis(indolyl)methanes under solvent free conditions using microwave irradiation and ultrasonicator heating in aqueous media. Vitamin B1 is an economical, non-toxic, nonflammable and water soluble green organocatalyst. Moreover, the simple approach, easily operational, short reaction time, high yield and using a little quantity of thiamine hydrochloride makes this method an alternative approach. Present protocol is a simple and eco-friendly approach for the synthesis of bis(indolyl)methanes under microwave and ultrasonicator conditions.

Synthesis and evaluation of novel sulfonamide analogues of 6/7-aminoflavones as anticancer agents via topoisomerase II inhibition.

A series of new sulfonamide analogues of 6/7-aminoflavones were synthesized by using molecular hybridization approach. These new sulfonamide analogues were screened for antiproliferative activity against human hepatocellular carcinoma (HepG-2), human lung cancer cell line (A-549), human colorectal adenocarcinoma (Caco-2) cancer cell lines. Compounds 5p, 5q, 5t, 5v, 5w and 5x exhibited good anticancer activity against selected cancer cell lines. These compounds were further evaluated to predict their ability to inhibit topoisomerase-II enzyme. Compound 5x has shown potent antiproliferative activity (IC50 value 0.98 µM) as compared to standard drug Adriamycin (IC50 = 0.94 µM) indicating that these compounds exhibits anticancer activity via inhibition of topoisomerase-II enzyme. Docking results also have supported above observations by indicating that compounds are held in the active pocket by combination of various hydrogen and hydrophobic interactions with Top II-DNA-etoposide enzyme.

Metal-Dependent Nucleobase Recognition by Picolinamide.

A C-nucleoside featuring picolinamide as the base moiety has been synthesized and incorporated in the middle of a DNA oligonucleotide. The melting temperatures of duplexes formed by this modified oligonucleotide with its unmodified counterparts placing either adenine, cytosine, guanine or thymine opposite to the picolinamide residue were found to be highly dependent on the identity and concentration of transition metal ions in the samples. For example, AgI uniquely promoted pairing with adenine and PdII with guanine. Pairing with cytosine, on the other hand, was retarded by all of the metal ions studied (AgI , CuII , HgII , NiII , PdII and ZnII ).

Crystal structure of (5R)-5-[(1S)-1,2-di-hydroxy-eth-yl]-4-meth-oxy-3-phenyl-2,5-di-hydro-furan-2-one.

In the title compound, C13H14O5, the furan ring is essentially planar [maximum deviation = 0.031 (3) Å] with a stereogenic center (R) at the sp (3) hybridized C atom. The C atom bearing the dihy-droxy ethyl group is S. The absolute configuration is based on the precursor in the synthesis. The two O-H groups are in an anti conformation with respect to each other. The mean plane of the furan-one group is twisted by 8.2 (4)° from that of the phenyl ring. In the crystal, mol-ecules are linked by O-H⋯O hydrogen bonds involving furan-one C=O groups and symmetry-related hy-droxy groups, forming a two-dimensional network parallel to (001). Weak C-H⋯O hydrogen bonds are observed within the two-dimensional network.

Design, synthesis, and preliminary in vitro and in vivo evaluation of N-(2-diethylaminoethyl)-4-[18F]fluorobenzamide ([18F]-DAFBA): a novel potential PET probe to image melanoma tumors.

In order to develop a PET radiopharmaceutical to image malignant melanoma, we synthesized N-(2-diethylaminoethyl)-4-[(18)F]fluorobenzamide ([(18)F]-DAFBA). In vitro studies show a high uptake of [(18)F]-DAFBA by the B16F1 melanoma cells. No significant binding was seen for DAFBA to the sigma-1 and sigma-2 receptors in vitro. The in vivo biodistribution studies performed in normal ICR mice showed a low uptake in the normal tissues followed by further elimination of radioactivity from these tissues with time. The biodistribution studies performed in C57 mice bearing the melanoma tumor xenograft showed a rapid uptake of radioactivity in the tumor that reached a plateau within 30 min postinjection. The F-18 uptake in the tumor was 7.00 +/- 2.76, 6.57 +/- 1.66, and 5.80 +/- 0.98%ID/g at 60, 120, and 180 min, respectively. A steady uptake of radioactivity in the tumor and low uptake in normal tissues resulted in high tumor to normal tissue ratios. For example, at 180 min postinjection, the tumor to tissue ratios were 14.90 +/- 6.47, 21.90 +/- 4.68, 32.91 +/- 6.11, 39.73 +/- 11.78, and 6.33 +/- 1.9, for the spleen, lungs, muscle, blood, and liver, respectively. The radioactivity rapidly cleared from the blood pool, and it decreased from 0.68 +/- 0.21%ID/g at 60 min to 0.13 +/- 0.03%ID/g at 180 min. The F-18 uptake in the bones at 60, 120, and 180 min was 0.91 +/- 0.27, 0.57 +/- 0.32, and 0.17 +/- 0.05%ID/g, respectively. This low uptake in the bones reflects its in vivo resistance toward defluorination. A low residual activity in normal tissues and a high tumor uptake signifies the superior imaging potential of this compound. Because of these positive traits, [(18)F]-DAFBA could help delineate the tumor and its metastases when used for imaging applications. Further in vivo studies are underway to assess the potential of [(18)F]-DAFBA as a promising PET imaging probe.

3-Amino-4-(2-((4-[18F]fluorobenzyl)methylamino)methylphenylsulfanyl)benzonitrile, an F-18 fluorobenzyl analogue of DASB: synthesis, in vitro binding, and in vivo biodistribution studies.

3-amino-4-(2[11C]methylaminomethylphenylsulfanyl)benzonitrile (C-11 DASB) exhibits excellent in vitro and in vivo properties toward the serotonin transporter. If labeled with a longer physical half-life radioisotope, this ligand could be more attractive to research groups lacking an on-site cyclotron or lacking C-11 synthesis capabilities. We produce p-[18F]fluorobenzyl iodide on a routine basis to synthesize several neuroimaging agents. Therefore, it was straightforward for us to substitute the DASB precursor with this prosthetic group and assess its biological properties. We designed a different synthesis strategy to obtain the DASB precursor (desmethyl DASB). Herein we report an efficient and facile synthetic route that provides higher chemical yields of 3-amino-4-(2-aminomethylphenylsulfanyl)benzonitrile and related analogues. In addition, we report our results from incorporating p-[18F]fluorobenzyl iodide in DASB precursor and its affect on the in vitro and in vivo biological properties of the DASB.