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Multi-target weapons: diaryl-pyrazoline thiazolidinediones simultaneously targeting VEGFR-2 and HDAC cancer hallmarks.

ABSTRACT: In anticancer drug discovery, multi-targeting compounds have been beneficial due to their advantages over single-targeting compounds. For instance, VEGFR-2 has a crucial role in angiogenesis and cancer management, whereas HDACs are well-known regulators of epigenetics and have been known to contribute significantly to angiogenesis and carcinogenesis. Herein, we have reported nineteen novel VEGFR-2 and HDAC dual-targeting analogs containing diaryl-pyrazoline thiazolidinediones and their in vitro and in vivo biological evaluation. In particular, the most promising compound 14c has emerged as a dual inhibitor of VEGFR-2 and HDAC. It demonstrated anti-angiogenic activity by inhibiting in vitro HUVEC proliferation, migration, and tube formation. Moreover, an in vivo CAM assay showed that 14c repressed new capillary formation in CAMs. In particular, 14c exhibited cytotoxicity potential on different cancer cell lines such as MCF-7, K562, A549, and HT-29. Additionally, 14c demonstrated significant potency and selectivity against HDAC4 in the sub-micromolar range. To materialize the hypothesis, we also performed molecular docking on the crystal structures of both VEGFR-2 (PDB ID: 1YWN) and HDAC4 (PDB-ID: 4CBY), which corroborated the designing and biological activity. The results indicated that compound 14c could be a potential lead to develop more optimized multi-target analogs with enhanced potency and selectivity.

SUBMITTER: Upadhyay N

PROVIDER: S-EPMC8459325 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:PurposeSimultaneously recorded electroencephalography and functional magnetic resonance imaging (EEG-fMRI) is highly informative yet technically challenging. Until recently, there has been little information about EEG data quality and safety when used with newer multi-band (MB) fMRI sequences. Here, we measure the relative heating of a MB protocol compared with a standard single-band (SB) protocol considered to be safe. We also evaluated EEG quality recorded concurrently with the MB protocol on humans.Materials and methodsWe compared radiofrequency (RF)-related heating at multiple electrodes and magnetic field magnitude, B1+RMS, of a MB fMRI sequence with whole-brain coverage (TR = 440 ms, MB factor = 4) against a previously recommended, safe SB sequence using a phantom outfitted with a 64-channel EEG cap. Next, 9 human subjects underwent eyes-closed resting state EEG-fMRI using the MB sequence. Additionally, in three of the subjects resting state EEG was recorded also during the SB sequence and in an fMRI-free condition to directly compare EEG data quality across scanning conditions. EEG data quality was assessed by the ability to remove gradient and cardioballistic artifacts along with a clean spectrogram.ResultsThe heating induced by the MB sequence was lower than that of the SB sequence by a factor of 0.73 ± 0.38. This is consistent with an expected heating ratio of 0.64, calculated from the square of the ratio of B1+RMS values of the sequences. In the resting state EEG data, gradient and cardioballistic artifacts were successfully removed using traditional template subtraction. All subjects showed an individual alpha peak in the spectrogram with a posterior topography characteristic of eyes-closed EEG. The success of artifact rejection for the MB sequence was comparable to that in traditional SB sequences.ConclusionsOur study shows that B1+RMS is a useful indication of the relative heating of fMRI protocols. This observation indicates that simultaneous EEG-fMRI recordings using this MB sequence can be safe in terms of RF-related heating, and that EEG data recorded using this sequence is of acceptable quality after traditional artifact removal techniques.

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Multi-target weapons: diaryl-pyrazoline thiazolidinediones simultaneously targeting VEGFR-2 and HDAC cancer hallmarks.

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