The natural product hymenialdisine was first isolated in 1980 from the marine sponges of the genera Hymeniacidon, Acanthella, Axinella and Pseudaxinyssa. The structure was elucidated on the basis of X-ray crystallography demonstrating a structurally interesting pyrrole-azepin-8-one ring system bonded to a glycocyamidine ring. Great interest has been taken in synthesizing this type of scaffold due to its potent activity in competitive kinase inhibition. In addition, several patents have claimed pharmacological use of these compounds for prevention and treatment of different diseases. The challenging syntheses of hymenialdisine and its analogues are described in this review as well as their evaluation as kinase inhibitors.

DNA damage induced by ionizing radiation activates the ataxia telangiectasia mutated pathway, resulting in apoptosis or DNA repair. The serine/threonine checkpoint kinase (Chk2) is an important transducer of this DNA damage signaling pathway and mediates the ultimate fate of the cell. Chk2 is an advantageous target for the development of adjuvant drugs for cancer therapy, because inhibition of Chk2 allows normal cells to enter cell cycle arrest and DNA repair, whereas many tumors bypass cell cycle checkpoints. Chk2 inhibitors may thus have a radioprotective effect on normal cells. We report herein a class of natural product derived Chk2 inhibitors, exemplified by indoloazepine 1, that elicit a strong ATM-dependent Chk2-mediated radioprotection effect in normal cells and p53 wt cells, but not p53 mutant cells (>50% of all cancers). This study represents the first example of a radioprotective effect in human cells other than T-cells and implicates a functional ATM pathway as a requirement for IR-induced radioprotection by this class of Chk2 inhibitors. Several of the hymenialdisine-derived analogues inhibit Chk2 at nanomolar concentrations, inhibit autophosphorylation of Chk2 at Ser516 in cells, and increase the survival of normal cells following ionizing radiation.

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Checkpoint kinase 2 is a serine/threonine protein which functions as an important transducer in apoptosis or DNA repair following activation by DNA damage. Inhibition of checkpoint kinase 2 is thought to sensitize p53-mutated or p53-deficient cancerous cells but protect normal tissue following DNA-damage caused by ionizing radiation or chemotherapeutic agents. The development of checkpoint kinase inhibitors for the treatment of cancer has therefore been a major objective in drug discovery over the past decade. Several inhibitors have been co-crystallized in the active site of checkpoint kinase 2 revealing important features of effective inhibitors. Some of these inhibitors have entered clinical trials in the last decade. This review describes and discusses the most recent inhibitors of checkpoint kinase 2 as reported in the literature, including an evaluation of biological activity.

This study aimed to develop docetaxel (DTX) loaded poly(lactic-coglycolic acid) (PLGA) nanoparticles (DTX-NPs) and to evaluate the different pharmacological sensitivity of NPs to MCF-7 and MDA-MB-231 breast cancer cells. NPs containing DTX or coumarin-6 were prepared by the nanoprecipitation method using PLGA as a polymer and d-α-tocopherol polyethylene glycol 1000 succinate (TPGS) as a surfactant. The physicochemical properties of NPs were characterized. In vitro anticancer effect and cellular uptake were evaluated in breast cancer cells. The particle size and zeta potential of the DTX-NPs were 160.5 ± 3.0 nm and -26.7 ± 0.46 mV, respectively. The encapsulation efficiency and drug loading were 81.3 ± 1.85% and 10.6 ± 0.24%, respectively. The in vitro release of DTX from the DTX-NPs was sustained at pH 7.4 containing 0.5% Tween 80. The viability of MDA-MB-231 and MCF-7 cells with DTX-NPs was 37.5 ± 0.5% and 30.3 ± 1.13%, respectively. The IC 50 values of DTX-NPs were 3.92-and 6.75-fold lower than that of DTX for MDA-MB-231 cells and MCF-7 cells, respectively. The cellular uptake of coumarin-6-loaded PLGA-NPs in MCF-7 cells was significantly higher than that in MDA-MB-231 cells. The pharmacological sensitivity in breast cancer cells was higher on MCF-7 cells than on MDA-MB-231 cells. In conclusion, we successfully developed DTX-NPs that showed a great potential for the controlled release of DTX. DTX-NPs are an effective formulation for improving anticancer effect in breast cancer cells.