A series of 1-ethyl-2,4-dioxo-(1H,3H)-quinazolin-3-yl amino acid and hydrazone derivatives were synthesized and tested for their antitumor activity. The alcohol and acid derivatives of quinazolindione were conjugated with the amino acid derivatives at N-3 site via ester or amide bonds by carbodiimide and azide methods. The carbodiimide-mediated amide and esterification steps were performed in the presence of HOBt or DMAP respectively otherwise the side-products N-acyl urea derivatives are formed, instead of the desired derivatives. Nine compounds exhibited encouraging antitumor activity against human liver carcinoma cell line (HepG2).
Some physiologically active amino acid and dipeptide esters were coupled to 3-(2-hydroxyethyl)-2,4-dioxo-(1H,3H)-quinazoline at N-1 via acetyl/propionyl link. The C2/C3 anchor segments were introduced by either alkylation or Michael addition reactions with ethyl chloroacetate or methyl acrylate respectively. The occurrence of these two reactions on nitrogen N-1 rather than oxygen atom was confirmed by spectral values ( 1 H and 13 C NMR). Amide bond formation was performed by the azide activation procedure at 0 o C to avoid Curtius rearrangement. 21 of the newly synthesized compounds exhibited IC50's in the range of 5.63-26.9 µg/mL relative to doxorubicin (3.23 µg/mL) when tested against HepG2cell line.
Unter optimalen Bedingungen werden die Aminosäuren (Ia)‐(II) mit Nicotinsäureazid (II) zu den N‐Nicotinoyl‐Derivaten (IIIa)‐(IIIl) umgesetzt; aus L‐Ornithin (Im) bzw. L‐Lysin (In) erhält man die Nα,Nδ‐ bzw. Nα,Nε‐diacylierten Säuren (IIIm) bzw. (IIIn).
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