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Inhibition of Colon Carcinogenesis*
Published in Herman Autrup, Gary M. Williams, Experimental Colon Carcinogenesis, 2019
An alternative method of inhibiting chemical carcinogenesis is to prevent the formation of the carcinogen. Vitamin C has been shown to suppress the formation of nitrosamines generated by reaction of nitrous acid with Oxytetracycline, morpholine, dimethylamine, piperazine, methylurea, and N-methylaniline.56 In a preliminary report provision of 1.2% ascorbic acid to the diet of DMH-treated SD rats reduced the colon tumor incidence to 38% compared to 64% in the unsupplemented control.47 The protective effect of Vc may be related to its ability to react directly with carcinogens,57 to block carcinogen activation,56 to suppress enzyme activities, or to enhance others as Vc does in MNNG stimulation of guanylate cyclase.58 Ascorbic acid may reverse early stages of carcinogenesis. In a human study Vc is reported to reduce the number of polyps in familial polyposis patients with multiple polyps who have undergone ileorectal anastomosis.59
Long-Term Effects: Cancer
Published in Ernest L. Abel, Smoking and Reproduction: An Annotated Bibliography, 2017
17.f.21. Pelkonen, O., Jouppila, P., and Karki, N. T., Effect of maternal cigarette smoking on 3,4-benzpyrene and n-methylaniline metabolism in human fetal liver and placenta, Toxicol. Appl. Pharmacol., 23, 399—407, 1972. Smoking during pregnancy did not affect fetal liver metabolism of benzo(a)pyrene, but placentas from mothers who smoked had benzo(a)pyrene hydroxylase activity during the first half of pregnancy at term. Duration of smoking required to induce such activity during pregnancy is about 10 to 11 weeks. There was no correlation between placenta and fetal liver benzo(a)pyrene hydroxylase activity.
Synthesis, biological activities and docking studies of pleuromutilin derivatives with piperazinyl urea linkage
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2021
Yuanyuan Zhang, Chuan Xie, Yang Liu, Feng Shang, Rushiya Shao, Jing Yu, Chunxia Wu, Xinghui Yao, Dongfang Liu, Zhouyu Wang
The piperazinyl urea linkage can be constructed with substituted amines via three strategies (Scheme 1). Pleuromutilin 1 was reacted with tosyl chloride and triethylamine in DCM to form pleuromutilin-22-O-tosylate 7 in 78.3% yield, which could convert to 22-(piperazine-1-yl)-22-deoxypleuromutilin 8 by treatment with NaI, piperazine and potassium carbonate in dry THF with a 75.2% yield. Compounds 6a ∼ e were synthesised by treating 7 with N-substituted-1-carboxamide 9a ∼ e in the presence of a catalytic amount of NaI and K2CO3 in MeCN with 78.3 ∼ 92.3% yield. Here, the primary amines 12a∼e reacted with bis(trichloromethyl)carbonate (BTC) or N, N'-carbonyldiimidazole (CDI) to form the corresponding isocyanate, which was used to form piperazinyl urea moiety by reacting with N-Boc-piperazine in the presence of triethylamine with 56.2 ∼ 82.3% yield. Afterwards, 9a ∼ e were obtained via removal of the above Boc protected group using trifluoroacetic acid (TFA) in 93.7 ∼ 97.2% yield. Compounds 6f ∼ u were synthesised in 45.6 ∼ 82.7% yield by treating 8 in the presence of potassium carbonate with substituted 2,2,2-trichloro-acetamide 10f∼u, which were acquired by reacting primary amines 12f∼u with trichloroacetyl chloride in DCM with 54.7 ∼ 97.2% yield. Moreover, in regard to the secondary amine, the expected product was rarely obtained using the above two strategies. N-methylaniline 12v was treated with 4-nitrophenyl carbonochloridate in the presence of N-methylmorpholine (NMM) in DCM to give 11, which was condensed without further purification and reacted with 22-(piperazine-1-yl)-22-deoxypleuromutilin 8 to form N-methyl derivative 6v in 40.5% yield. Additionally, 6w∼z were synthesised from corresponding Boc-protected amine and nitro molecules (Scheme 2). 6w was gained from deprotecting 6g in the presence of TFA in 95.6% yield, and two other amine derivatives 6x and 6y were attained by stannous chloride reduction of 6d and 6p in 92.5% and 75.5% yields, respectively. 6y was used to react with chloracetyl chloride to get 14 in the presence of triethylamine with 70.1% yield, which was treated with morpholine to produce 6z in 50.3% yield.