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  • We recently described the benzoxazin

    2019-10-09

    We recently described the 1,3-benzoxazin-4-one analogue of LY294002 and showed it to have pan-PI3K and DNA-PK activity [2]. We have also reported on the activity of other family members, such as 3 which causes sensitization of lung cancer and colon cancer cells to radiation [11] and 4 (LTUSI122) as an inhibitor of angiogenesis [12]. Based on the cumulative evidence of our previously published work, we hypothesize that the 1,3-benzoxazine nucleus, with its altered electronic structure compared to the other scaffolds will retain the general binding capabilities for PI3K family members but will show modified selectivity profiles compared to its isosteric scaffolds and therefore represents an opportunity to discover more selective ligands at targets of interest. Here we report on the development of improved syntheses of the class, giving access to a series of compounds that show such modified selectivity profiles. We identified 20k (LTURM34), a potent DNA-PK inhibitor with improved selectivity compared to the chromone homologue NU7441 as well as 20i (LTURM36), a PI3Kδ selective compound. Both compounds show antiproliferative activity against a range of cancer cell lines.
    Results and discussion
    Conclusion In this work the synthesis of 3-bromo-2-hydroxybenzoic CCT245737 10 was improved and was used to synthesise 8-bromo-1,3-benzoxazine 11, 8-bromo-2-morpholino-1,3-benzoxazines 17 and 8-aryl-2-morpholino-1,3-benzoxazines 20. Modified conditions of Suzuki coupling were used to synthesise the 8-aryl, 8-aryl-6-chloro, and 6-aryl-2-morpholino-1,3-benzoxazines 20–22, the DNA-PK and PI3K inhibition % and some IC50 data of 31 compounds were measured. The DNA-PK activity (IC50 = 0.034 μM) for compound 20k (LTURM34) (dibenzo[b,d]thiophen-4-yl) was 170.6 fold more selective against the PI3K activity. From this result compound 20k (LTURM34) can be considered as a specific DNA-PK inhibitor. Furthermore, Compound 20i (8-(naphthalen-1-yl)) was a potent and selective PI3Kδ inhibitor with which could explain the high growth inhibition (GI = 92% at 10 μM) against the renal cancer cell line A498.
    Experimental
    Acknowledgments
    Glioblastoma multiforme (GBM) is the most aggressive and rapidly fatal type of brain tumors in adults . The prognosis of patients with GBM is extremely poor with a median survival of approximately 12months. Since 1978, patients with GBM have been treated by debulking surgery (to the extent that is safely feasible) and postoperative radiotherapy . The addition of chemotherapy to radiotherapy results only in a small survival benefit . Most frequently used chemotherapy, temozolomide, given concomitantly and in the adjuvant setting after radiotherapy, has increased median survival time of GBM patients only to 14.6months . Although temozolomide has shown to improve the treatment outcome of GBM, the use of this chemotherapeutic agent has not been uniform in all countries due to small survival benefit and high acquisition costs. Local radiotherapy has been for a long time a mainstay of standard treatment of GBM patients. In contrast to radiotherapy-induced excellent local control rates in most solid tumors, nearly all GBM patients (99%) die due to locally recurrent disease . Recent analyses have shown that vast majority of patients suffer from brain recurrence within or immediately adjacent to the high-dose radiation (60Gy) volumes , , . Moreover, local recurrences are also described after very high doses such as 90Gy . This shows that GBM is by nature one of the most radioresistant tumors, and with the use of postoperative radiotherapy, only disease stabilization for few months can be achieved. Therefore, there is an urgent need to find reasons for extreme radioresistance of GBM and to find new treatment strategies to improve the chance of survival of this rapidly fatal disease. Molecular basis of radioresistance involves many processes, including changes in growth factors and their receptors, different signaling and apoptotic pathways and DNA repair mechanisms . Whether higher tumor levels of DNA repair enzymes contribute to worse treatment results of GBM patients after postoperative radiotherapy was tested in the present study. For this, two DNA repair enzymes: poly-ADP ribose polymerase-1 (PARP-1) and DNA protein kinase (DNA-PK) were evaluated.