Synthesis and Biological Evaluation of Novel Uracil Derivatives as Thymidylate Synthase Inhibitors.

Cell division is driven by nucleic acid metabolism, and thymidylate synthase (TYMS) catalyzes a rate-limiting step in nucleotide synthesis. As a result, thymidylate synthase has emerged as a critical target in chemotherapy. 5-Fluorouracil (5-FU) is currently being used to treat a wide range of cancers, including breast, pancreatic, head and neck, colorectal, ovarian, and gastric cancers The objective of this study was to establish a new methodology for the low-cost, one-pot synthesis of uracil derivatives (UD-1 to UD-5) and to evaluate their therapeutic potential in BC cells. One-pot organic synthesis processes using a single solvent were used for the synthesis of drug analogues of Uracil. Integrated bioinformatics using GEPIA2, UALCAN, and KM plotter were utilized to study the expression pattern and prognostic significance of TYMS, the key target gene of 5-fluorouracil in breast cancer patients. Cell viability, cell proliferation, and colony formation assays were used as in vitro methods to validate the in silico lead obtained. BC patients showed high levels of thymidylate synthase, and high expression of thymidylate synthase was found associated with poor prognosis. In silico studies indicated that synthesized uracil derivatives have a high affinity for thymidylate synthase. Notably, the uracil derivatives dramatically inhibited the proliferation and colonization potential of BC cells in vitro. In conclusion, our study identified novel uracil derivatives as promising therapeutic options for breast cancer patients expressing the augmented levels of thymidylate synthase.

Outcomes of extra oral versus intraoral approach for Mandibular angle fracture reduction.

OBJECTIVE: To compare the outcomes of intraoral versus extraoral approach in the treatment of mandibular angle fracture. METHODS: The randomised controlled trail was conducted at the Department of Maxillofacial Surgery, Mayo Hospital, Lahore Pakistan, from September 2016 to March 2017, and comprised patients of mandibular angle fracture who were divided into two equal extraoral group A and intraoral group B. . Baseline and post-operative data on 1st and 7th days as well as 3 months following the surgery was collected. Data was analysed using SPSS 20. RESULTS: Of the 100 patients, there were 50(50%) in each of the two groups. Mean age of group A was 32.28±7.79 years compared to 33.72±8.13 years in group B. There were 39 (78%) males in group A and 36(72%) in group B. The mean pain score at baseline in the groups was not significantly different (p=0.795). On the 7th day and 3 months post-operation, mean pain score was significantly lower in group A (p=0.002). Nerve complication in group A was significantly high compared to group A (p=0.005). CONCLUSIONS: Extra oral approach for the management of mandibular angle fracture is better with regards to pain while intra-oral approach is less associated with nerve complications.