131I Induced In Vivo Proteolysis by Photoswitchable azoPROTAC Reinforces Internal Radiotherapy.

Photopharmacology, incorporating photoswitches such as azobenezes into drugs, is an emerging therapeutic method to realize spatiotemporal control of pharmacological activity by light. However, most photoswitchable molecules are triggered by UV light with limited tissue penetration, which greatly restricts the in vivo application. Here, this study proves that 131I can trigger the trans-cis photoisomerization of a reported azobenezen incorporating PROTACs (azoPROTAC). With the presence of 50 µCi mL-1 131I, the azoPROTAC can effectively down-regulate BRD4 and c-Myc levels in 4T1 cells at a similar level as it does under light irradiation (405 nm, 60 mW cm-2). What's more, the degradation of BRD4 can further benefit the 131I-based radiotherapy. The in vivo experiment proves that intratumoral co-adminstration of 131I (300 µCi) and azoPROTC (25 mg kg-1) via hydrogel not only successfully induce protein degradation in 4T1 tumor bearing-mice but also efficiently inhibit tumor growth with enhanced radiotherapeutic effect and anti-tumor immunological effect. This is the first time that a radioisotope is successfully used as a trigger in photopharmacology in a mouse model. It believes that this study will benefit photopharmacology in deep tissue.

Design, synthesis and biological evaluation of novel 4-(pyrrolo[2,3-d]pyrimidine-4-yloxy)benzamide derivatives as potential antitumor agents.

Cancer is a major cause of death worldwide. Small molecule inhibitors have become a major therapeutic treatment for cancer. In this study, a series of novel 4-(pyrrolo[2,3-d]pyrimidine-4-yloxy)benzamide derivatives were designed, synthesized and evaluated for their antitumor activity against the A549, Hela and MCF-7 cell lines. Among them, the optimal compound 35 was found to possess excellent inhibitory activity against the A549, Hela and MCF-7 cell lines with IC50 values of 5.29 ± 0.58, 3.72 ± 0.91, and 9.23 ± 0.56 µM, which were superior to Golvatinib. The structure-activity relationship showed that the introduction of 7H-pyrrolo[2,3-d]pyrimidine along with the F atom of the central and terminal benzene was beneficial to the improvement of inhibitory activity of the target compounds. Besides, we took further study on the combined mode between compound 35 and c-Met kinase through molecular docking.

Design, synthesis and biological evaluation of 4-(pyridin-4-yloxy)benzamide derivatives bearing a 5-methylpyridazin-3(2H)-one fragment.

A series of 4-(pyridin-4-yloxy)benzamide derivatives bearing a 5-methylpyridazin-3(2H)-one fragment were designed, synthesized, and evaluated for their biological activity. Most compounds showed effective inhibitory activity against cancer cell lines of A549, HeLa and MCF-7. Among them, the most promising compound 40 showed excellent activity against A549, HeLa and MCF-7 cell lines with IC50 values of 1.03, 1.15 and 2.59 µM, respectively, which was 2.606.95 times more active than that of Golvatinib. The structure-activity relationships (SARs) showed that the introduction of 5-methylpyridazin-3(2H)-one to "5-atom linker" and the modification of the amide with morpholine group were beneficial for enhancing the inhibitory activity of compounds. In addition, the further research on compound 40 mainly include c-Met kinase activity, concentration dependence, apoptosis (acridine orange staining), and molecular docking.

Discovery of novel pyrrolo[2,3-b]pyridine derivatives bearing 4-oxoquinoline moiety as potential antitumor inhibitor.

A series of pyrrolo[2,3-b]pyridine derivatives bearing 4-oxoquinoline moiety were designed, synthesized and evaluated for the anti-proliferative on three cancer cell lines (A549, HepG2 and MCF-7) in vitro. Most of the compounds showed moderate to high potency. Some excellent compounds were tested for the inhibitory activity of c-Met kinase. Compound 34 (c-Met IC50 = 17 nM) was investigated the selectivity against Flt-3, c-Kit, VEGFR-2, ALK, PDGFR-ß and RON. Structure-activity relationship studies indicated that hydrogen, fluorine atom, and mono-electron-withdrawing groups (mono-EWGs, such as R2 = F) on R, R1 and R2, respectively, were beneficial for the anti-proliferative activities of the target compounds. Besides, we have took further study on the combined mode between compound 34 and c-Met kinase through molecular docking.

Design, Synthesis, and Biological Evaluation of Pyridineamide Derivatives Containing a 1,2,3-Triazole Fragment as Type II c-Met Inhibitors.

A series of 4-(pyridin-4-yloxy)benzamide derivatives containing a 1,2,3-triazole fragment were designed, synthesized, and their inhibitory activity against A549, HeLa, and MCF-7 cancer cell lines was evaluated. Most compounds exhibited moderate to potent antitumor activity against the three cell lines. Among them, the promising compound B26 showed stronger inhibitory activity than Golvatinib, with IC50 values of 3.22, 4.33, and 5.82 µM against A549, HeLa, and MCF-7 cell lines, respectively. The structure-activity relationships (SARs) demonstrated that the modification of the terminal benzene ring with a single electron-withdrawing substituent (fluorine atom) and the introduction of a pyridine amide chain with a strong hydrophilic group (morpholine) to the hinge region greatly improved the antitumor activity. Meanwhile, the optimal compound B26 showed potent biological activity in some pharmacological experiments in vitro, such as cell morphology study, dose-dependent test, kinase activity assay, and cell cycle experiment. Finally, the molecular docking simulation was performed to further explore the binding mode of compound B26 with c-Met.

Discovery of novel 2-substituted-4-phenoxypyridine derivatives as potential antitumor agents.

A series of 2-substituted-4-phenoxypyridine derivatives were designed, synthesized, and evaluated for their antiproliferative activity against 4 cancer cell lines (A549, HT-29, H460, and U87MG) in vitro. Most compounds showed moderate to excellent potency. Nine tyrosine kinases (c-Met, Flt-3, ALK, VEGFR-2, VEGFR-3, PDGFR-α, PDGFR-ß, c-Kit, and EGFR) were used to evaluate the inhibitory activities with the most promising analogue 39, which showed the Flt-3/c-Met IC50 values of 2.18/2.61 nM. Structure-activity relationship studies indicated that n-Pr served as R1 group showed a higher preference, and stronger mono-EWGs on the phenyl ring (such as R2 = 4-F) was benefited to the potency.

Discovery of thinopyrimidine-triazole conjugates as c-Met targeting and apoptosis inducing agents.

Five series of N-methylpicolinamide moiety and thienopyrimidine moiety bearing triazole (21-26, 27-34, 35-41, 42-47 and 48-54) were designed and synthesized. And all the target compounds were evaluated for the IC50 values against three cancer cell lines (A549, HepG2 and MCF-7) and some selected compounds (43, 49 and 52) were further evaluated for the activity against c-Met, Flt-3, VEGFR-2, c-Kit and EGFR kinases. Moreover, SARs and docking studies indicated that thieno[3,2-d]pyrimidine bearing triazole moiety was privileged structure for the activity. Especially, the Cl atom on the 4-C position of aryl group showed the best activity. The most promising compound 49 showed 3.7-5.4-fold more activity than the lead drug Foretinib against A549, HepG2 and MCF-7 cell lines, with the IC50 values of 0.9 ±â€¯0.1 µM, 0.5 ±â€¯0.1 µM and 1.1 ±â€¯0.2 µM, respectively. And The experiments of enzyme-based showed that 49 inhibitor the c-Met selectively, with the IC50 values of 16 nM, which showed equal activity to Foretinib (14 nM). What's more, According to the result of AO single staining and Annexin V/PI staining, it's claimed that the 49 could induce late apoptosis of HepG2 cells and by a concentration-dependent manner.

Design, synthesis and biological evaluation of 7H-pyrrolo[2,3-d]pyrimidine derivatives containing 1,8-naphthyridine-4-one fragment.

In this study, a series of pyrrolo [2,3-d]pyrimidine derivatives containing 1,8-naphthyridine-4-one fragment were synthesized and their biological activity were tested. Most of the target compounds displayed moderate to excellent activity against one or more cancer cell lines and low activity against human normal cell LO2 in vitro. The most promising compound 51, of which the IC50 values were 0.66 µM, 0.38 µM and 0.44 µM against cell lines A549, Hela and MCF-7, shown more remarkable activity and better apoptosis effect than the positive control Cabozantinib. The structure-activity relationships (SARs) indicated that double-EWGs (such as R3 = 2-Cl-4-CF3) on the terminal phenyl rings was a key factor in improving the biological activity. In addition, the further research on compound 51 mainly included c-Met kinase activity and selectivity, concentration dependence, and molecular docking.

Synthesis and antiproliferative activity of 6,7-disubstituted-4-phenoxyquinoline derivatives bearing the 1,8-naphthyridin-2-one moiety.

A series of 6,7-disubstituted-4-phenoxyquinoline derivatives bearing the 1,8-naphthyridin-2-one moiety were designed, synthesized and evaluated for their biological activities. The target compounds exhibited moderate to high antiproliferative activity against three cancer cell lines (A549, HepG2 and MCF-7) and several compounds (25, 27, 33, 37, 41, 43, 49 and 53) were evaluated for the activity against c-Met kinase. The most promising compound 33 (IC50 c-Met = 2.36 nM) showed excellent activity against A549, HepG2 and MCF-7 cell lines with IC50 values of 0.23 µM, 0.42 µM and 0.21 µM, respectively, which was 1.5-2.1 times of the positive control. Furthermore, compound 33 was evaluated for the activity against Flt3, PDGFR-α, PDGFR-ß, c-Kit, Flt4, ALK and EGFR kinase. Structure activity relationship studies indicated that mono-EWGs (such as R2 = F) at 4-position of moiety C was a key factor in improving the antitumor activity. In addition, further research on compound 33 was mainly including concentration dependence, apoptosis (acridine orange staining), apoptosis result analyzing and molecular docking.