Azobenzene-3,3'-dicarboxylic acid exists in photoisomerizable (E) and (Z)-forms. Deprotonation of the carboxylic acid groups from the (E)-form occurs simultaneously, whereas in the (Z)-form it occurs in a stepwise fashion. The mono anionic form of the (Z)-isomer acts as a glycosidase mimic that proceeds through a general acid-general base catalytic mechanism. This is the first example of a photoresponsive glycosidase mimic.
Noscapine, a phthalide isoquinoline
alkaloid isolated from the
opium poppy Papaver somniferum, is
traditionally being used as an anticough drug. With a safe in vitro
toxicological profile, noscapine and its analogues have been explored
to show microtubule-regulating properties and anticancer activity
against various mammalian cancer cell lines. Since then, our group
and other research groups worldwide are working on developing new
noscapinoids to tap its potential as the leading drug molecule. With
our continuing efforts, we herein present synthesis and anticancer
evaluation of a series of imidazothiazole-coupled noscapinoids 7a–o and 11a–o. Natural α-noscapine
was N-demethylated to nornoscapine 4 and then reacted with 4-(chloromethyl) thiazole-2-amine. The resultant
noscapinoid 5 was coupled with various bromomethyl ketones 10a–o to give N-imidazothiazolyl noscapinoids 7a–o in very good yields. Similarly, natural α-noscapine 1 was O-demethylated using sodium azide/sodium
iodide, reacted with 4-(chloromethyl)thiazole-2-amine, and coupled
with bromomethyl ketones 10a–o to result in O-imidazothiazolyl noscapinoids 11a–o. All the new analogues 7a–o and 11a–o were fully characterized by their NMR and mass spectral analysis.
In vitro cytotoxicity assay was performed for compounds 5, 7a–o, 9, and 11a–o against
four different cancer cell lines: HeLa (cervical), MIA PaCa-2 (pancreatic),
SK-N-SH (neuroblastoma), and DU145 (prostate cancer). Among these
conjugates, 5, 7a, 9, 11b, 11c, 11e, and 11o showed potent cytotoxicity with low IC50 values. Further,
flow cytometry analysis revealed that MIA PaCa-2 cells treated with
these compounds induced cell cycle G2/M-phase arrest. In addition, Western blot analysis revealed that the cells treated
with these conjugates accumulate tubulin in the soluble fraction and
also elevate cyclin-B1 protein expression levels. Moreover, the conjugates
also increased the expression of caspase-3 and PARP levels which is
indicative of apoptotic cell death. In silico molecular docking studies
showed several noncovalent interactions like van der Waals and hydrogen-bonding
with tubulin protein and with good binding energy. The results indicated
that these noscapine analogues may serve as novel compounds that can
possibly inhibit tubulin protein and can be considered for further
optimization as a clinical candidate for treating pancreatic cancer.
A convenient synthesis of novel prototypes containing the two pharmacophores of chromene and 1,2,3-triazole in a single molecular backbone, were evaluated againstMycobacterium tuberculosisH37Rv strain.
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