Synthesis and Cytotoxic Activity of 5-Benzoylhexahydropyrimidine Derivatives

Abstract

The reaction of ethyl benzoylacetate with formaldehyde and natural amino acid ester hydrochlorides in acetate buffer (AcONa/AcOH, pH 4.0) at room temperature afforded 41-61% of new 5-benzoylhexahydropyrimidine derivatives. The synthesized compounds were evaluated for their in vitro cytotoxic activity against normal (HEK293) and tumor cell lines (Jurkat, HepG2). T-Lymphoblastic leukemia Jurkat cells turned out to be most sensitive to the examined hexahydropyrimidine derivatives. Ethyl 5-benzoyl-1,3-bis[2-ethoxy-1-(4-hydroxy benzyl)-2-oxoethyl]hexahydropyrimidine-5-carboxylate showed the highest cytotoxic activity against all tested cell lines.

Anticancer Activity of Mannich Bases: A Review of Recent Literature

“…The use of esters of amino acids as amine reagents in a double Mannich reaction at the carbon atom adjacent to the carbonyl group in ethyl acetoacetate or in the related primary amide afforded hexahydropyrimidines 13 (Figure 1), whose in vitro cytotoxic activity was poor to moderate (IC 50 =58 μM against Jurkat cancer cells and IC 50 =88 μM against SHSY5Y cancer cells for the compound 13 derived from the ethyl ester of ʟ‐tyrosine as the most potent compound in the series) [27] . The scope of the reaction was further expanded to include fluorinated substrates such as ethyl 4,4‐difluoro‐3‐oxobutanoate, 1,1‐difluoropentane‐2,4‐dione or 1,1,5,5‐tetrafluoropentane‐2,4‐dione [28] or ethyl benzoylacetate, [29] but the antiproliferative activity of these compounds against Jurkat and HepG2 cancer cells was again generally modest, although the hexahydropyrimidine obtained from the Mannich condensation of ethyl benzoylacetate with formaldehyde and the ethyl ester of ʟ‐tyrosine had IC 50 close to 9 μM against Jurkat cells [29] . In a distinct note, the final products that were isolated from the Mannich reaction between acetophenones, formaldehyde and isopropylamine hydrochloride were piperidinols 14 (Figure 1), and four of these compounds (Ar=4‐BrC 6 H 4 , 4‐H 3 COC 6 H 4 , C 6 H 5 , thiophen‐2‐yl) had IC 50 values around 10 μM against Huh7 human hepatoma, while only the activity of compound 14 (Ar=4‐BrC 6 H 4 ) was comparable to that of 5‐fluorouracil (IC 50 =7 μM) against T47D breast cancer cells [30] .…”

“…[27] The scope of the reaction was further expanded to include fluorinated substrates such as ethyl 4,4-difluoro-3-oxobutanoate, 1,1-difluoropentane-2,4-dione or 1,1,5,5-tetrafluoropentane-2,4-dione [28] or ethyl benzoylacetate, [29] but the antiproliferative activity of these compounds against Jurkat and HepG2 cancer cells was again generally modest, although the hexahydropyrimidine obtained from the Mannich condensation of ethyl benzoylacetate with formaldehyde and the ethyl ester of �-tyrosine had IC 50 close to 9 μM against Jurkat cells. [29] In a distinct note, the final products that were isolated from the Mannich reaction between acetophenones, formaldehyde and isopropylamine hydrochloride were piperidinols 14 (Figure 1), and four of these compounds (Ar = 4-BrC 6 H 4 , 4-H 3 COC 6 H 4 , C 6 H 5 , thiophen-2-yl) had IC 50 values around 10 μM against Huh7 human hepatoma, while only the activity of compound 14 (Ar = 4-BrC 6 H 4 ) was comparable to that of 5-fluorouracil (IC 50 = 7 μM) against T47D breast cancer cells. [30] Finally, a series of ketonic Mannich bases 15 (Figure 1), that were synthesized from 2-(acetylamino)benzothiazoles as substrates and fluoroquinolones as amine reagents, have been tested against human lung cancer cell line A-549 with generally poor results.…”