Novel Lipophilic Hydroxyurea Derivatives: Synthesis, Cytostatic and Antiviral Activity Evaluations

Abstract

The novel hydroxyurea derivatives of l- and d-amino acid amides 5a-l were prepared by aminolysis of N-(1-benzotriazolecarbonyl)-amino acid amides 4a-f with O-benzylhydroxylamine and N-methylhydroxylamine and evaluated for their antiviral and cytostatic activity against malignant tumor cell lines and normal human fibroblasts. Compounds 5a, 5c, 5e and 5k showed the highest antiproliferative effects against all tumor cell lines tested. The strongest non-specific cytostatic activities against HeLa cells were affected by compounds 5a, 5c, 5e and 5k on MCF-7 cells by 5c, 5e and 5k and MIA PACa-2 cells by 5c and 5k. Differential effects at micromolar concentrations were observed for compounds 5a, 5c, 5e, 5k and 5l in Hep G2 cells, for compounds 5c, 5e, 5k and 5l in PC-3 cells and for compounds 5e, 5k and 5l in SW 620 cells.

Antitumor Mechanisms of Amino Acid Hydroxyurea Derivatives in the Metastatic Colon Cancer Model

“…We have previously shown that BOU and MHCU exerted the strongest antiproliferative effect upon a panel of tested cell lines, including the metastatic colon cancer cell line SW620 [6,7]. Tested compounds are both amino acid derivatives of HU, with the same amide moiety and a different amino acid part: BOU is a d -phenylglycine and MHCU is a l -phenylalanine derivative.…”

“…These processes are connected to down-regulation of colorectal cancer malignancy biomarkers TAGLN2 and Gal-3 [21,22] as well as the metastatic phenotype marker PAI-RBP1 [23]. In conclusion, down-regulation of specific CRC proteins involved in tumor progression and invasion might explain the selective activity of BOU on the metastatic SW620 cell line in comparison with other tested tumor cell lines derived from solid tumors [6]. Moreover, it seems that cell death mechanisms might be triggered by metabolic changes and oxidative stress through activation of caspase 7 and down-regulation of two crucial oxidative stress-protecting proteins, DJ-1 and PRDX3, in treated SW620 cells (Table S2 in Supplementary Information).…”

“…However, their biological effects were not described in scientific literature, with the exception of our previous report on cell growth inhibition activities [6]. Class I HDAC isoforms are highly expressed in colorectal carcinomas, particularly in the proliferating, de-differentiated tumors [26].…”

“…Similarly, Perkovic et al . [6] synthesized a series of novel l - and d -amino acid amide HU derivatives and evaluated their antiviral and cytostatic activity against malignant tumor cell lines, including leukemia and normal human fibroblasts [6]. In this paper, we report the biological mechanisms of action in vitro , in silico and in vivo of two compounds showing favorable, specific and concentration-dependent antiproliferative effects.…”

Benzotriazole as a Synthetic Auxiliary

“…23 Benzotriazole moiety in compounds 27 was readily replaced with amines or hydroxylamines affording ureidoamides 29 and hydroxyureidoamides 30. [24][25][26] Ureidoamides 31 were prepared directly from chlorides 25 with excess of 2-aminoethanol, 3-aminopropanol and 5-aminopentanol. 27 On the other hand, amidation of chlorides 25 with N-phenylhydroxylamine gave hydroxamic acids 33, which readily cyclized to oxadiazines 34 (Scheme 4).…”