Three crucial anticancer
scaffolds, namely indolin-2-one, 1,3,4-thiadiazole,
and aziridine, are explored to synthesize virtually screened target
molecules based on the c-KIT kinase protein. The stem cell factor
receptor c-KIT was selected as target because most U.S. FDA-approved
receptor tyrosine kinase inhibitors bearing the indolin-2-one scaffold
profoundly inhibit c-KIT. Molecular hybrids of indolin-2-one with
1,3,4-thiadiazole (
IIIa
–
m
) and aziridine
(
VIa
and
VIc
) were afforded through a modified
Schiff base green synthesis using β-cyclodextrin-SO
3
H in water as a recyclable proton-donor catalyst. A computational
study found that indolin-2,3-dione forms a supramolecular inclusion
complex with β-cyclodextrin-SO
3
H through noncovalent
interactions. A molecular docking study of all the synthesized compounds
was executed on the c-KIT kinase domain, and most compounds displayed
binding affinities similar to that of Sunitinib. On the basis of the
pharmacokinetic significance of the aryl thioether linkage in small
molecules, 1,3,4-thiadiazole hybrids (
IIIa
–
m
) were extended to a new series of 3-((5-(phenylthio)-1,3,4-thiadiazol-2-yl)imino)indolin-2-ones
(
IVa
–
m
) via thioetherification using
bis(triphenylphosphine)palladium(II)dichloride as the catalyst for
C–S bond formation. Target compounds were tested against NCI-60
human cancer cell lines for a single-dose concentration. Among all
three series of indolin-2-ones, the majority of compounds demonstrated
broad-spectrum activity toward various cancer cell lines. Compounds
IVc
and
VIc
were further evaluated for a five-dose
anticancer study. Compound
IVc
showed a potent activity
of IC
50
= 1.47 μM against a panel of breast cancer
cell lines, whereas compound
VIc
exhibited the highest
inhibition for a panel of colon cancer cell lines at IC
50
= 1.40 μM.
In silico
ADME property descriptors
of all the target molecules are in an acceptable range. Machine learning
algorithms were used to examine the metabolites and phase I and II
regioselectivities of compounds
IVc
and
VIc
, and the results suggested that these two compounds could be potential
leads for the treatment of cancer.
Background
In the current study, a simple, improved, precise, rapid, and accurate reverse phase liquid chromatographic method was produced for the estimation of dalfampridine in bulk and tablet dosage form which is a potassium channel blocker used for the treatment of multiple sclerosis (MS). The separation of dalfampridine was achieved isocratically on a C18 column (250 × 4.6 mm, 5 μm) using (0.1% v/v) buffer pH 3.0 ± 0.05 adjusted with diluted orthophosphoric acid (OPA) and acetonitrile (ACN) in the ratio of 60:40% (v/v) as a mobile phase, at a flow rate of 0.5 mL/min, and column temperature of 40 °C. HPLC grade methanol as diluents was used. Five microliters of the standard solution of the drug was injected, and the eluted analytes were detected at 262 nm.
Results
Dalfampridine was eluted at 4.5 min with a run time of 10 min. Linearity in the method was measured in the concentration range of 25–75 ppm with a correlation coefficient of 0.999. Limit of detection and limit of quantitation were found to be 0.711 μg/mL and 2.154 μg/mL, respectively. Dalfampridine was subjected for forced degradation stability study in conditions of thermal, acid, alkali, and oxidation and photo-degradation condition. The degradants were well resolved from the dalfampridine main peak. Validation of the developed method is carried as per USFDA and ICH guidelines.
Conclusion
The results of the analysis prove that the method is simple, improved, precise, accurate, and rapid for estimating the content of dalfampridine in bulk drug and tablet dosage form and can be applied for routine analysis.
Cancer stem cells (CSCs) are the cells in a primary tumor that have the opportunity to self-renew as well as differentiate into certain cell types, thus forming a mixed tumor. CSCs have been shown to be involved in every aspect of cancer development, including tumor initiation, proliferation, and metastatic activity; they are also involved in chemotherapeutic drug resistance and the recurrence of certain cancers. Based on these capabilities, CSCs have been explored as the next target for the treatment and management of cancer. Salinomycin (SAL), a polyether ionophore antibiotic being used in the poultry industry, was identified as a powerful anti-cancer compound that possesses broad-spectrum activities, especially against CSCs. Here we point out the noteworthy work reported on SAL’s mechanism of action, anticancer activities, toxicity, and clinic applications. In addition, SAL derivatives synthesized by different research groups and their biological activity will also be highlighted.
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