Synthesis of cytotoxic derivatives of 2-oxo-1-azetidinylacetamide

Abstract

New derivatives of 2-oxo-1-azetidinylacetamide have been synthesized by the four-component condensation of β-amino acids with aldehydes and isonitriles. Study of their cytotoxic activity in vitro revealed a cytotoxic effect of individual compounds in relation to cancer cells of human fibrosarcoma, mouse hepatoma, and mouse neuroblastoma. activity.In a continuation of investigations devoted to the synthesis of 1,3,4-trisubstituted β-lactams and to the analysis of the interconnection between their structure and cytotoxic properties [1-3], we have selected derivatives of 2-oxo-1-azetidinylacetamide as the next subject.The Ugi one-step four-component condensation of β-amino acids with aldehydes and isonitriles [4-7] was used for their preparation. Its advantage in comparison with other methods of obtaining 2-oxo-1azetidinylacetamide is the possibility of the simultaneous introduction of substituents directed into the 3C and 4C positions of the heterocycle, and also of replacing protons in the methylene and amide fragments of acetamide.The synthesis of the new azetidinones 4a-j with the aid of this condensation was effected by the interaction of structural analogs of β-amino acids 1a-e, aldehydes 2a-e, and isocyanates 3a,b (Scheme 1).The condensation was carried out in methanol at room temperature during 3-5 days. The end of the reaction was checked by TLC. Substances were isolated from the reaction mixtures by column chromatography. Their structures were demonstrated by 1 H NMR spectra, elemental analysis, and their homogeneity by HPLC.The structural specificity of this reaction is characterized by the formation of a chiral center at the C-5 atom of the resulting compounds 4a-j. Additional chiral centers are formed at the C-3 and C-4 atoms of 4a-i due to the presence of substituents in the αand β-positions of the initial amino acids 1b-e. Theoretically this must lead to the preparation of the final product as a complex diastereoisomeric mixture. However, judging by HPLC data and 1 H NMR spectra the majority of the isolated products were equilibrium mixtures of only two isomers. In the case of azetidinone 4f their ratio proved to be displaced in the direction of one representative (1:4), but azetidinones 4h and 4j proved to be diastereoisomeric products. __________________________________________________________________________________________

Microwave-assisted facile synthesis of 2-azetidinone derivatives and evaluation of their antitumor activities

“…(2) Coy等 [24] 报道了1,4-二芳基取代的氮 杂环丁酮的合成, 并测试了其对人类神经母细胞瘤细 胞的细胞毒性. (3) Lukevics等 [25] 通过Ugi三组分反应 合成了新型的氮杂环丁酮类衍生物(图2), 并研究了对 人源纤维肉瘤细胞、鼠源肝癌细胞和鼠源成神经细胞 瘤三株细胞系的体外细胞毒性. 含氮杂环化合物在生物医药领域具有重要的作 用 [26] , 其中含苯并咪唑化合物 [27] 和喹喔啉类化合物 [28] 具有广泛的生物活性.…”

Synthetic Approaches toward Monocyclic 3‐Amino‐β‐lactams

“…The cyclocondensation of β‐amino acid 144 , formaldehyde ( 145 ) and isocyanides 146 has been reported to result, after rearrangement via an acyl transfer, in 3‐azido‐β‐lactams 148 (Scheme ) . Carboxylic acids containing Cbz‐ or Boc‐protected amino groups at the α‐position instead of an azido group, can also be converted …”

“…[117] Carboxylic acids containing Cbz-or Boc-protected amino groups at the a-position instead of an azido group, can also be converted. [118] In addition to the discussed methods for b-lactam synthesis, severalo ther approaches are availablef or the construction of this four-membered heterocycle,for example, through cycloaddition of vinyl ethers with isocyanates and the carbonylation of aziridines.H owever,t hese strategies have not been applied for the synthesis of 3-aminoazetidin-2-ones, and are therefore not mentioned in this Review.…”

Diversity Oriented Syntheses of Conventional Heterocycles by Smart Multi Component Reactions (MCRs) of the Last Decade

“…Tri-substituted azetidinone 4 is formed easily from β-amino acids by an Ugi-4F3CR in 32–42% yield ( Scheme 3 ) [ 30 ]. Thereby two functions amino- and carboxylic acid-groups are located in one component β-amino acid.…”