Efficient T3P mediated synthesis, differential cytotoxicity and apoptosis induction by indolo-triazolo-thiadiazoles in human breast adenocarcinoma cells
Authors: Dhanya Sunil
Pooja R Kamath
Shubhankar Das
B S Satish Rao
Abdul Ajees Abdul Salam
Journal: Chemico-biological interactions (2017)
Discipline: PHARMACOLOGY & TOXICOLOGY
Keywords: Apoptosis; Cell cycle; Cytotoxicity; Docking; Indolo-triazolo-thiadiazole.
Affiliations: Department of Chemistry, Manipal Institute of Technology, Manipal University, 576 104, Karnataka, India., Department of Chemistry, Manipal Institute of Technology, Manipal University, 576 104, Karnataka, India. Electronic address: ., Department of Radiation Biology & Toxicology, School of Life Sciences, Manipal University, 576 104, Karnataka, India., Department of Atomic and Molecular Physics, Manipal University, 576 104, Karnataka, India.

Abstract:  The limited efficacy of marketed anticancer agents demands the design of novel target-specific hybrid molecules incorporating multiple bioactive pharmacores to combat cancer. In the present study, a one-pot simple and efficient T3P® mediated procedure for the preparation of twelve new 3-(substituted- [1,2,4]triazolo[3,4-b] [1,3,4]thiadiazolo)-1H-indoles with short reaction times, easy workup procedure, good yields, and purity of products is described. Cytotoxicity assay (MTT), flow-cytometric univariate cell cycle analysis, Annexin V-FITC staining and DNA fragmentation for cell death mechanism suggested that compound 3d with chloro-substituted phenyl ring induced enhanced cytotoxicity by an apoptotic pathway with high differential toxicity to breast adenocarcinoma cells (MCF-7) when compared with normal human dermal fibroblast cells. Additionally, the interaction between the BH3 domain of anti-apoptotic proteins Bcl-2 and Bcl-xL with the pharmacophore 3d was examined by molecular docking simulations to assess its potential to induce apoptosis. The docking solutions were proposed to explain the observed selectivity of 3d to Bcl-xL protein. From the present findings, the lead compound, 3d exhibited better anticancer activity when related to the other synthesized molecules with specific action on MCF-7 cells and hence can be considered as a plausible candidate chemo-therapeutic agent, although this warrants further experimentation. 

Retracted: No

PubPeer comments:
 Interesting observation: For all compounds C, H, N showed higher values than calculated for molecular formula. Than there is predictable trend. For Carbon 0.10-0.20 higher, for hydrogen 0.01-0.02 higher and nitrogen 0.02-0.03...!!! In any normal experiment, at least in some cases should have been lower. I guess the compounds are not pure enough. Can authors explain. If 1H and 13 NMR images are shared fro 3a-3l is shared, would be much useful. I also believe it would be very difficult to assign the peaks as authors did for different protons of the compounds using 400MHz NMR. 3a: Anal. Calcd. For C19H15N5OS: C, 63.14; H, 4.18; N, 19.38; found: 63.21; H, 4.20; N, 19.39. 3b: Anal. Calcd. for C20H17N5OS: C, 63.98; H, 4.56; N,18.65; found: C, 64.13; H, 4.57; N, 18.67. 3c: Anal. Calcd. for C21H19N5OS: C, 64.76; H, 4.92; N, 17.98; found: C, 64.95; H, 4.93; N, 17.80. 3d: Anal. Calcd. for C19H14N5ClOS: C, 57.65; H, 3.56; N, 17.69; found: C, 57.85; H, 3.57; N, 17.71. 3e: Anal. Calcd. For C20H16N5ClOS: C, 58.60; H, 3.93; N, 17.09; found: C, 58.71; H, 3.94; N, 17.11. 3f: Anal. Calcd. for C21H18N5ClOS: C, 59.50; H, 4.28; N, 16.52; found: C, 59.73; H, 4.29; N, 16.54. 3g: Anal. Calcd. for C22H16N6OS: C, 64.06; H, 3.91; N, 20.38; found: C, 64.19; H, 3.92; N, 20.40. 3h: Anal. Calcd. for C23H18N6OS: C, 64.77; H, 4.25; N, 19.70; found: C, 64.87; H, 4.26; N, 19.73. 3i: Anal. Calcd. for C22H15N6ClOS: C, 59.12; H, 3.38; N, 18.80; found: C, 59.31; H, 3.39; N, 18.83. 3k: Anal. Calcd. For C23H17N6ClOS: C, 59.93; H, 3.72; N, 18.23; found: C, 60.11; H, 3.73; N, 18.26. 3l: Anal. Calcd. for C24H19N6ClOS: C, 60.69; H, 4.03; N, 17.69; found: C, 60.77; H, 4.04; N, 17.72. , 
 Can authors share the spectra of all compounds. It appears from the data that the compounds are not pure. How to account for higher values of CHN in ALL compounds? Is it normal in chemical research? overall spectral data not convincing regarding their purity in the absence of original images , 
 T3P cannot be used for this kind of cyclisation reactions. It is a very weak reagent, instead we POCl3 or other similar reagent. Authors need to clarify as one of the paper which claimed to have used this reagent has already been retracted due to issues with NMR and other data. , 
  T3P cannot be used for this kind of cyclisation reactions. It is a very weak reagent, instead we POCl3 or other similar reagent. I disagree, T3P should be quite suitable for the N-acylation, and the dehydrative cyclization that follows does not pose particular problems. An example for an acylation-cyclization sequence (not the same, but in principle similar) can be found here: 10.1021 ol303073b. Intramolecular dehydrative cyclization was e.g. shown in WO99 37620 You cannot just state  cannot be used for this kind of cyclisation reactions without giving additional evidence, e.g., by citing a paper where this was shown to be a problem. Concerning the elemental analysis data: yes, data of a certain geographical provenience often show strangely consistent patterns. ,