News Update on Dihydropyrimidine Research: Aug – 2019

Recent Advances in the Biginelli Dihydropyrimidine Synthesis. New Tricks from an Old Dog

In 1893, P. Biginelli rumored the synthesis of functionalized three,4-dihydropyrimidin-2(1H)-ones (DHPMs) via three-component condensation reaction of AN aromatic organic compound, urea, and alkyl radical acetoacetate. within the past decade, this long-neglected multicomponent reaction has intimate an interesting revival, principally thanks to the fascinating pharmacologic properties related to this dihydropyrimidine scaffold. during this Account, we have a tendency to highlight recent developments within the Biginelli reaction in areas like solid-phase synthesis, combinatorial chemistry, and natural product synthesis. [1]

Dihydropyrimidine dehydrogenase and the efficacy and toxicity of 5-fluorouracil

The identification of genetic factors related to either responsiveness or resistance to 5-fluorouracil (5-FU) therapy, in addition as genetic factors predisposing patients to the event of severe 5-FU-associated toxicity, is more and more being recognised as a very important field of study. Dihydropyrimidine dehydrogenase (DPD) is that the initial and rate-limiting accelerator within the biological process of 5-fluorouracil (5-FU). though the role of tumoral levels as a prognostic issue for clinical responsiviness has not been firmly established, there’s ample proof that a deficiency of DPD is related to severe toxicity when the administration of 5-FU. [2]

Colorectal Tumors Responding to 5-Fluorouracil Have Low Gene Expression Levels of Dihydropyrimidine Dehydrogenase, Thymidylate Synthase, and Thymidine Phosphorylase

We had antecedently shown that top cistron expressions (mRNA levels) of thymidylate synthase (TS; Leichman et al., J. Clin. Oncol., 15: 3223–3229, 1997) and nucleoside phosphorylase (TP; Metzger et al., Clin. Cancer Res., 4: 2371–2376, 1998) in pretreatment tumour biopsies may establish tumors that will be nonresponsive to 5-fluorouracil (5-FU)-based medical care. during this study, we have a tendency to investigated the association between intratumoral organic phenomenon of the pyrimidine katabolism accelerator dihydropyrimidine dehydrogenase (DPD) and therefore the response of large intestine tumors to identical 5-FU-based protocol. DPD expressions were measured by quantitative reverse transcription-PCR in thirty three pretreatment biopsies of large intestine tumors from patients WHO went on to receive treatment with 5-FU and leucovorin (LV). [3]

Dihydropyrimidine dehydrogenase deficiency and fluorouracil-related toxicity

Dihydropyrimidine dehydrogenase (DPD) is that the initial and rate-limiting accelerator of 5-fluorouracil (5-FU) katabolism. we tend to report white cell DPD information regarding a gaggle of fifty three patients (23 men, 30 women, mean age fifty eight, vary 36–73), treated by 5-FU-based therapy in several French establishments and UN agency developed out of the blue 5-FU-related toxicity. WBC samples (standard assortment procedure) were sent to United States for DPD determination (biochemical method). Among the complete cluster of fifty three patients, nineteen had a big DPD deficiency (DD; below a hundred and fifty fmol min–1 mg–1 supermolecule, i.e. but seventieth of the mean determined from previous population study). [4]

In Silico Analysis for DPYD Gene and the Effect of the Mutation on Dihydropyrimidine Dehydrogenase Enzyme

Aim: The aim of this study was to implement AN in silico bioinformatics analysis for clinically ascertained missense variants in human DPYD sequence to research the result these variants on Dihydropyrimidine dehydrogenase catalyst ‘s structure and performance.

Methods: The human DPYD sequence was investigated in dbSNP/NCBI, 273238 SNPs were found; 99645 SNPs were Homo sapins; of that 534 were missense SNPs. Missense SNPs were selected  for in silico analysis; SIFT, Polyphen2, SNPs & GO, Imutant 2.0, Mutation 3D , UCSF Chimera and HOPE were accustomed investigate the result of SNPs on DPD protein’s structure and performance. [5]

Reference

[1] Kappe, C.O., 2000. Recent advances in the Biginelli dihydropyrimidine synthesis. New tricks from an old dog. Accounts of Chemical Research, 33(12), pp.879-888. (Web Link)

[2] van Kuilenburg, A.B., 2004. Dihydropyrimidine dehydrogenase and the efficacy and toxicity of 5-fluorouracil. European journal of cancer, 40(7), pp.939-950. (Web Link)

[3] Salonga, D., Danenberg, K.D., Johnson, M., Metzger, R., Groshen, S., Tsao-Wei, D.D., Lenz, H.J., Leichman, C.G., Leichman, L., Diasio, R.B. and Danenberg, P.V., 2000. Colorectal tumors responding to 5-fluorouracil have low gene expression levels of dihydropyrimidine dehydrogenase, thymidylate synthase, and thymidine phosphorylase. Clinical Cancer Research, 6(4), pp.1322-1327. (Web Link)

[4] Dihydropyrimidine dehydrogenase deficiency and fluorouracil-related toxicity
G Milano, M C Etienne, V Pierrefite, M Barberi-Heyob, R Deporte-Fety & N Renée
British Journal of Cancervolume 79, pages627–630 (1999)  (Web Link)

[5] M. Elrashid, A., Y. Basher, M., A. Gharib, A. I., A. I. Alfaki, M., Mohammed, N. M., M. Elmoselhy, A., G. Elbager, S. and Khalil, S. I. (2018) “In Silico Analysis for DPYD Gene and the Effect of the Mutation on Dihydropyrimidine Dehydrogenase Enzyme”, Journal of Advances in Medical and Pharmaceutical Sciences, 16(3), pp. 1-10. doi: 10.9734/JAMPS/2018/40300. (Web Link)

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