AMINO ALKYLPHOSPHINIC ACIDS AND DERIVED PEPTIDES

氨基酸类似物的合成，其中酸性磷单元 取代羧酸基一直是研究的一个领域 二十多年了。这些类似物，以及衍生的多肽 将它们结合在一起，显示出各种生物效应，如酶 抑制、除草活性和抗菌作用。而当 这些化合物中的大多数是自然产生的α-的类似物- 在多肽和蛋白质中发现的氨基酸，一直以来都有一些兴趣 贝塔和伽马类似物也是如此。在很大程度上，模拟开发已经 重点研究了二元膦酸[Rp(O)(OH)2]。直到最近， 人们对源自单音节的类比兴趣较少。 膦酸[R2P(O)OH]，即使这些化合物看起来 在结构上更类似于自然产生的氨基酸。穿着那些 已调查的案件中，几种氨基烷基膦酸和 含有它们的多肽确实显示出抗菌和其他生物效应 活动。因此，该项目的长期目标是综合 附加的氨基烷基膦酸以及二肽和三肽 含有这些基于磷的氨基酸类似物。 该项目将专注于对现有合成方法的修改，以 适用于以前未曾用作 模拟开发中的衬底。具体地说，要使用的酰胺 是三价酰胺酯[烷基烷基膦酰胺，RP(OR‘)NR112]， 它将使用商业上成熟的方法来制备 可用的前驱物质。这些酰胺酯将与N- 卤代烷基邻苯二甲酰亚胺在Arbuzov反应中提供相应的 邻苯二甲酰亚胺。联氨去除邻苯二甲酰基的研究 而醋酸也应该裂解酸敏感的P-N键 膦酰胺部分，从而生成所需的氨基烷基膦 酸。根据使用的特定邻苯二甲酰亚胺衍生物，α、β 或获得伽马-氨基酸类似物。这些类比与 适当保护的氨基羧酸和相关的二肽 偶联剂，如二环己基碳二亚胺，将提供 各自的二肽和三肽类似物。氨基烷基膦酸类 以及含磷多肽类似物将被测试以 确定预期生物活动的性质和程度 这些化合物展示了。

The synthesis of amino acid analogs wherein an acidic phosphorus unit replaces the carboxylic acid group has been an area of investigation for more than twenty years. These analogs, and the derived peptides incorporating them, exhibit a variety of biological effects such as enzyme inhibition, herbicidal activity and antibacterial action. While the majority of these compounds are analogs of the naturally occurring alpha- amino acids found in peptides and proteins, there has been some interest in beta and gamma analogs as well. To a large extent, analog development has focused on the dibasic phosphonic acids [RP(O)(OH)2]. Until recently, there had been less interest in analogs derived from the monobasic phosphinic acids [R2P(O)OH], even though these compounds would seem to be structurally more similar to the naturally occurring amino acids. In those cases which have been investigated, several aminoalkylphosphinic acids and peptides incorporating them do show antibacterial and other biological activity. Thus, the longterm objective of this project is the synthesis of additional aminoalkylphosphinic acids as well as the di- and tripeptides containing these phosphorous-based amino acid analogs. This project will focus on modifications of existing synthetic methods for application to phosphorus amides which have not previously been used as substrates in analog development. specifically, the amides to be employed are the trivalent amidoesters [alkyl alkylphosphonamidites, RP(OR')NR112], which will be prepared using established methods from commercially available precursors. These amidoesters will be combined with N- haloalkylphthalimides in an Arbuzov reaction to afford the corresponding phthalimidophosphinamides. Removal of the phthaloyl group with hydrazine and acetic acid should also cleave the acid sensitive P-N linkage of the phosphinamide moiety, thereby generating the desired aminoalkylphosphinic acids. Depending on the specific phthalimide derivative used, alpha, beta or gamma-amino acid analogs are obtained. Coupling of these analogs with suitably protected aminocarboxylic acids and related dipeptides by use of a coupling agent such as dicyclohexylcarbodiimide will afford the respective di- and tripeptide analogs. The aminoalkylphosphinic acids as well as the phosphorus-containing peptide analogs will be tested to ascertain the nature and degree of anticipated biological activity that these compounds exhibit.