Carbamoylation at C-8 position of natural 3-arylcoumarin scaffold for the discovery of novel PARP-1 inhibitors with potent anticancer activity.

Structural modification based on natural privileged scaffolds has proven to be an attractive approach to generate potential antitumor candidates with high potency and specific targeting. As a continuation of our efforts to identify potent PARP-1 inhibitors, natural 3-arylcoumarin scaffold was served as the starting point for the construction of novel structural unit for PARP-1 inhibition. Herein, a series of novel 8-carbamyl-3-arylcoumarin derivatives were designed and synthesized. The antiproliferative activities of target compounds against four BRCA-mutated cancer cells (SUM149PT, HCC1937, MDA-MB-436 and Capan-1) were evaluated. Among them, compound 9b exhibited excellent antiproliferative effects against SUM149PT, HCC1937 and Capan-1 cells with IC50 values of 0.62, 1.91 and 4.26 µM, respectively. Moreover, 9b could significantly inhibit the intracellular PARP-1/2 activity in SUM149PT cells with IC50 values of 2.53 nM and 6.45 nM, respectively. Further mechanism studies revealed that 9b could aggravate DNA double-strand breaks, increase ROS production, decrease mitochondrial membrane potential, arrest cell cycle at G2/M phase and ultimately induce apoptosis in SUM149PT cells. In addition, molecular docking study demonstrated that the binding mode of 9b with PARP-1 was similar to that of niraparib, forming multiple hydrogen bond interactions with the active site of PARP-1. Taken together, these findings suggest that 8-carbamyl-3-arylcoumarin scaffold could serve as an effective structural unit for PARP-1 inhibition and offer a valuable paradigm for the structural modification of natural products.

Chalcone-Based Synthesis of Tetrahydropyridazines via Cloke-Wilson-Type Rearrangement-Involved Tandem Reaction between Cyclopropyl Ketones and Hydrazines.

A facile and efficient approach for the synthesis of multisubstituted tetrahydropyridazines starting from cyclopropyl ketones and hydrazines has been developed. The transformation is chalcone-based and takes place via a Cloke-Wilson-type rearrangement-involved tandem reaction catalyzed by TfOH in HFIP.

Discovery of novel benzamide derivatives bearing benzamidophenyl and phenylacetamidophenyl scaffolds as potential antitumor agents via targeting PARP-1.

Poly(ADP-ribose) polymerase-1 (PARP-1) plays a crucial role in DNA damage repair and has been identified as a promising therapeutic target in cancer therapy. As a continuation of our efforts on the development of novel PARP-1 inhibitors with potent anticancer activity, a series of benzamide derivatives containing the benzamidophenyl and phenylacetamidophenyl scaffolds were designed and synthesized based on the structure optimization of our previously reported compound IX. All target compounds were screened for their in vitro antiproliferative activities against human colorectal cancer cells (HCT116, DLD-1 and SW480) and human normal colonic epithelial cells (NCM460). Among them, compound 13f exhibited the most potent anticancer activity against HCT116 cells and DLD-1 cells with IC50 = 0.30 µM and 2.83 µM, respectively. Moreover, 13f displayed significant selectivity in inhibiting HCT116 cancer cells over the normal NCM460 cells. Furthermore, 13f exhibited excellent PARP-1 inhibitory effect with IC50 = 0.25 nM. Besides, 13f was found to effectively inhibit colony formation and migration of HCT116 cells. Studies on the mechanisms revealed that 13f could arrest cell cycle at G2/M phase, accumulate DNA double-strand breaks, reduce mitochondrial membrane potential and ultimately induce apoptosis in HCT116 cells. In addition, molecular docking study indicated that 13f could combine firmly with the catalytic pocket of PARP-1 through multiple hydrogen bond interactions. Collectively, these findings demonstrated that 13f could serve as a promising anticancer candidate and deserves further investigation.

Design, synthesis, biological evaluation and molecular docking study of novel urea-based benzamide derivatives as potent poly(ADP-ribose) polymerase-1 (PARP-1) inhibitors.

Poly(ADP-ribose) polymerase-1 (PARP-1) is one of the key members of DNA repair enzymes that is responsible for the repair of DNA single-strand breaks. Inhibition of PARP-1 has been demonstrated to be a promising strategy to selectively kill tumor cells by targeting DNA repair pathway. Herein, a series of novel urea-based benzamide derivatives were designed and synthesized based on the structure-based drug design strategy. The anticancer activities against five human cancer cell lines including HCT116, MDA-MB-231, HeLa, A579 and A375 were evaluated and the preliminary structure-activity relationships were summarized. Among them, compounds 23f and 27f exhibited potent antiproliferative effects against HCT116 cells with IC50 values of 7.87 µM and 8.93 µM, respectively. Moreover, both compounds displayed excellent PARP-1 inhibitory activities with IC50 values of 5.17 nM and 6.06 nM, respectively. Mechanistic investigations showed that 23f and 27f could effectively inhibit colony formation and cell migration of HCT116 cells. Furthermore, 23f and 27f could cause cell cycle arrest at G2/M phase, and induce apoptosis by upregulating the expression of Bax and cleaved Caspase-3 and downregulating the expression of Caspase-3 and Bcl-2 in HCT116 cells. In addition, molecular docking studies provided the rational binding modes of these compounds in complex with PARP-1. Collectively, these results suggested that 23f and 27f could serve as promising drug candidates for further investigation.

Synthesis of ß-cyclodextrin-PEG-G molecules to delay tumor growth and application of ß-cyclodextrin-PEG-G aggregates as drug carrier.

The clinical use of many chemotherapeutic drugs is considerably greatly limited due to their serious side effects. This problem can be solved by using a low-toxic or nontoxic drug carrier that exhibits excellent performance in entrapping chemotherapeutic drugs. Accordingly, ß-cyclodextrin-PEG-guanosine (ß-CD-PEG-G) molecule was first synthesized. The molecules can self-assemble into negatively charged spherical aggregates (called ß-CD-PEG-G aggregates) that can stably exist in an aqueous solution and entrap doxorubicin (Dox) to form ß-CD-PEG-G-Dox nanomedicine. Dox encapsulation efficiency is approximately 79 ± 6.3%. Dox from ß-CD-PEG-G-Dox nanomedicine exhibits sustained release and pH responsiveness. Cell and animal experiments showed that ß-CD-PEG-G-Dox nanomedicine could effectively induce cancer cell apoptosis to exert antitumor activity. Unexpectively, the animal experiment and tissue sections demonstrated that ß-CD-PEG-G aggregates exhibit certain antitumor activity that could delay the tumor growth. Therefore, the ß-CD-PEG-G molecule has high potential as a drug carrier candidate.

Construction of a Drug Delivery System and Photodynamic Therapy Reagent Based on the Biotin-HSA-DDA-TCPP Molecules and the Application of Synergistic Antitumor Effect.

A biotin-HSA-DDA-TCPP molecule, which can be used as a photodynamic therapeutic agent and drug carrier, was synthesized. The molecule can self-assemble into spherical aggregates, which can be loaded with Dox to form biotin-HSA-DDA-TCPP-Dox nanoparticles in aqueous solution, and the Dox loading efficiency was 86.6 ± 1.76%. The Dox's release behavior was pH responsive and has a sustained release. Cell experiments showed that biotin-HSA-DDA-TCPP-Dox nanoparticles could effectively induce cancer cell apoptosis to exert anticancer and photodynamic therapy effects. The results of animal experiments, tissue sections, and blood biochemistry tests showed that the biotin-HSA-DDA-TCPP-Dox nanoparticles could exert the effect of photodynamic therapy and antitumor, which is similar to Dox after laser irradiation, and achieve a synergistic antitumor effect. The nanoparticles can significantly reduce the Dox toxicity and increase the circulation time of the drug in the body. In summary, the biotin-HSA-DDA-TCPP molecule, which combines the advantages of photodynamic therapy and drug carrier, has great potential in clinical application.

Preparation of ß-CD-DPPE-Dox Nanomedicine and Its' Application as the Anticancer and Antitumor Drug.

ß-CD-DPPE molecule was synthesized through the conjugation of ß-CD-NH2 and the DPPE molecule, and its' water-solubility was more excellent than the traditional phospholipid molecule. The spherical micelles was formed by ß-CD-DPPE molecule in aqueous solution, and the ß-CD-DPPE-Dox nanomedicine can be prepared through loading Dox (Doxorubicin) into the micelles, and the Dox loading ratio was about 82.3 ± 7.27%. At the same time the Dox release behavior from the nanomedicine was sustained-release and pH controlled release, and the release test in vitro showed that the release rate of the Dox at the lower pH was faster than that of normal pH (pH = 7.4), which indicated that the rate of release in the tumor microenvironment is faster than in the normal tissue. Biological test showed that the micelles was low cytotoxicity, and the cytotoxicity of ß-CD-DPPE-Dox nanomedicine was lower than the Dox under the same Dox concentration, and the ß-CD-DPPE-Dox nanomedicine could effectively induce cancer cell apoptosis and inhibit the tumor growth.

A liposome preparation based on ß-CD-LPC molecule and its application as drug-delivery system.

AIM: The ß-CD-LPC molecule was synthesized based on the conjugation of LPC and ß-CD molecules and it could self-assemble into liposome which was used to encapsulate the Dox to form nanomedicine for the cancer therapy. MATERIALS & METHODS: The anticancer and antitumor effect of ß-CD-LPC-Dox nanomedicine was studied with the vitro and vivo experimental methods. RESULTS: The result showed that ß-CD-LPC liposome had high Dox drug-loading rate and a good sustained-release effect. Cell experiment showed that the ß-CD-LPC-Dox nanomedicine could effectively induce cancer cell apoptosis and in vivo experiments showed that ß-CD-LPC-Dox liposome could effectively inhibit tumor growth and had an effective anticancer activity with lower biotoxicity. CONCLUSION: The ß-CD-LPC-Dox nanomedicine could be applied as a candidate drug to therapy the cancer.