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    • br Introduction The structural similarities between puromyci

    2023-05-24


    Introduction The structural similarities between puromycin (1, Fig. 1) and the aminoacyl adenyl terminal of aminoacyl–tRNA allow it to terminate the protein synthesis process by causing premature release of a polypeptide from the ribosome [1], [2]. Tremendous progress in the study of puromycin and related structures for the optimization of their antibiotic effects has been described over past several decades [3], [4]. However, the antibiotic efficacy of puromycin and related derivatives suffered due to their inability to distinguish between protein synthesis in normal healthy cells and compromised, diseased cells [5], [6], [7]. In prior studies we have considerably reported upon the structure–activity relationship for puromycin related compounds as antibiotic agents [8], [9], [10], [11]. Herein, we present our studies on the lesser–explored property of puromycin–based compounds as inhibitors of peptidases [12]. We sought to restrict inhibition of protein synthesis in the design of the desirable compounds to obtain better toxicity–profiles for the studied analogs. Given that Puromycin–Sensitive Aminopeptidase (PSA) is among the most important aminopeptidases being studied for implications on leukemia [13], [14], we have explored the efficacy against PSA enzyme as a measure of the potency of synthesized compounds. Various analogs with structures based on the puromycin template were synthesized and studied for the inhibition of aminopeptidases. Aminopeptidases represent a class of metalloenzymes (usually zinc) that mediate the cleavage of 5720 near the N–terminal of peptides [15]. The pleiotropic nature of aminopeptidase enzymes manifests with broad implications in various medical conditions such as Alzheimer's disease [16], Parkinson's disease [17], angiogenesis [18], diabetes [19], and Huntington's disease [20]. These metalloenzymes also play a crucial role in antigen presentation on the major histocompatibility complex (MHC) class I molecules [21]. However, the most direct implication of aminopeptidases has been noted in the modulation of cancerous malignancies [22], [23], [24]. The upregulation of aminopeptidases and amino acid transporters [25] in cancer cells provides support to this thesis [26]. The inhibition of aminopeptidase mediated intracellular peptide degradation has been utilized to block the supply chain of recycled free amino acids [27]. Depletion of amino acids in cells stimulates amino acid deprivation response (AADR) [28]. For example, the induction of nutrient stress by administering asparagine synthetase inhibitors has been described as a viable option for combating acute lymphoblastic leukemia (ALL) [29]. Interestingly, compared to normal cells, malignant cells have higher sensitivity to the absence of specific amino acids, leaving them vulnerable to apoptosis and a diminished rate of proliferation [30]. Seminal work by Wheatly and coworkers highlighted this difference along with the mechanism for this selectivity by analyzing the effects of nutrient deprivation on various malignant cell lines. While human fibroblasts showed ability to reach quiescence (G0) under nutritionally stressful conditions, cell lines with malignant phenotypes tried to continue the cell cycle leading to mitotic catastrophe and cell death [31]. This absence of stringent control at the G1 checkpoint of the cell cycle in malignant cell lines affords a potential to be exploited in selectively targeting them via the modulation of their nutrition supply. This should allow healthy cells to continue to proliferate unaffectedly. Krige and coworkers later reported utilizing this principle in the development of a new inhibitor of aminopeptidases for the treatment of acute myeloid leukemia (AML) [32]. Krige et al. included the well–known aminopeptidase inhibitor, bestatin (2, Fig. 1) for comparison while presenting the discovery of the prodrug, tosedostat (3, Fig. 1) [33]. Tosedostat is currently in phase II of clinical evaluation for its efficacy in the treatment of refractory and relapsed AML [34].