脯氨酸衍生物及類似物

簡介

脯氨酸是一種非極性的蛋白質氨基酸，當加入縮氨酸時會形成叔酰胺。它的酰胺基上沒有氫基，因此不能作為氫鍵供體。脯氨酸是蛋白質和縮氨酸中螺旋結構和薄片結構的典型破壞者。¹

在產生蛋白質的氨基酸中，脯氨酸扮演著特殊的角色。在蛋白質結構中，平面肽鍵主要發生在 反式 構象中。² 脯氨酸殘基限制了肽鏈的構象空間。然而，由於 順式 和反式Xaa-Pro鍵異構體間的自由焓差很小，只有2.0 kJ-mol^-1 （相對於10.0 kJ-mol^-1 for other Xaa-non-Pro peptide bonds)，在 RT 時有相對較高的 30% cis conformation 的本質機率，並且 cis 和 trans 異構體都存在於溶液中。^3,4

Pro殘基N端側肽鍵的 順式/反式異構化在蛋白質的折疊過程中扮演了關鍵的角色，因為 順式/反式異構化的旋轉障礙是由於 順式/反式異構化的旋轉障礙所造成的。nbsp;順/反異構化的旋轉障礙相當高（85,0 ± 10,0 kJ-mol^-1）。因此，這種相互轉換被描述為蛋白質折疊的限制步驟之一 體外 和 體內。⁵ 在自然界中有一類酵素，即肽基-脯氨酰-順/反式-異構酶（PPIases）。^6-8

使用脯氨酸類似物進行的比較研究顯示，肽基-脯氨酰鍵順式/反式異構化催化的關鍵步驟是降低平面共轭 C-N 酰胺鍵的雙鍵特性。任何能削弱酰胺鍵的雙鍵特性的因素，例如使平面肽鍵不穩定或使脯氨酰氮的雜化從 sp²  移動到 sp³，都會加速異構化。^9,10

為了瞭解肽的亞胺鍵幾何形狀與生物活性之間的關係，^11,12 已開發出提供 Xaa-Pro 亞胺構象限制的合成脯氨酸類似物。這些脯氨酸類似物基於烷基和芳香基團的環取代、環中加入雜原子或脯氨酸環的擴展或收縮（表 1）。這些類似物有希望用於構象研究，以及調節天然存在的  以及全新設計的線性和環狀多肽的生物、藥物或物理化學特性。

限制 Xaa-Pro Imide 形態的脯氨酸類似物或同源物結構

表 1.
IUPAC 命名法
	α-methyl-L-proline	(2R)-2-methyl-pyrrolidine-2-carboxylic acid
	α-benzyl-L-proline <	(2R)-2-benzyl-pyrrolidine-2-carboxylic acid	(2R)-2-benzyl-pyrrolidine-2-carboxylic acid
	trans-4-hydroxy-L-proline <	(2S,4R)-4- 羥基吡咯烷-2-羧酸
	cis-4-hydroxy-L-proline <	(2S,4S)-4- 羥基吡咯烷-2-羧酸
	trans-3-hydroxy-L-proline <	(2S,3R)-3- 羥基吡咯烷-2-羧酸
	cis-3-hydroxy-L-proline <	(2S,3S)-3- 羥基吡咯烷-2-羧酸
	trans-4-amino-L-proline <	(2S,4R)-4- 氨基吡咯烷-2-羧酸
	3,4-dehydro-DL-proline	(±)-3-pyrrolin-2-carboxylic acid
	L-2-Aziridinecarboxylic-acid	L-2-Aziridinecarboxylic acid	(2S)-aziridine-2-carboxylic acid
	L-2-Azetidinecarboxylic-acid	(2S)-azetidine-2-carboxylic acid
	L-pipecolic acid	(2S)-piperidine-2-carboxylic acid
	4-oxa-L-proline	(4S)-thiazolidine-4-carboxylic acid
	3-thia-DL-proline	thiazolidine-2-carboxylic acid
	4-thia-L-proline	(4R)-thiazolidine-4-carboxylic acid [TB1]

自然界中存在數種脯氨酸類似物和同系物。¹³ 脯氨酸和羥脯氨酸的各種3-和4-烷基化衍生物以及具有環限制的類似物，如氮丙啶-2-羧酸和氮杂环丁烷-2-羧酸，以及環擴展，即哌啶醇酸。例如哌啶醇酸，這些都可以在天然產品中找到。^14,15 衍生物如L-氮杂环丁烷-2-羧酸、 顺式-4-羟基-L-脯氨酸和3,4-脱氢-DL-脯氨酸可防止原胶原折叠成稳定的三螺旋构象，从而减少纤维化过程中胶原的过度沉积和肿瘤的生长。¹⁶

噻唑烷-4-羧酸硫代脯氨酸也被納入膠原蛋白模型化合物^17,18 和其他生物活性分子，如凝血酶抑制劑、¹⁹ ；^20,21 二肽基肽酶IV底物，²² 血管張力素II，²³ HIV 抑制劑、²⁴ ACE 抑制劑、²⁵ 和催產素。²⁶

α 甲基脯氨酸是一種生物活性分子，可恢復骨膠原 I 型合成的正常水平。²⁷ 它可以被看作是構象受限的氨基異丁酸類似物。 α甲基脯氨酸殘基已被插入嗎啡肽中，以進行 Xaa-Pro cis-/trans-isomers 生物活性的構象研究。²⁸ A α-甲基脯氨酸含有潛在的雙 α₄β₁ 整合素拮抗劑。²⁹

α苄基脯氨酸結合了脯氨酸衍生物的構象限制和苯丙氨酸的電子特性。含有 α-苄基-脯氨酸亞基結構的螺旋內酰胺已被合成為潛在的 beta-turn 模仿劑。

材料

抱歉，發生意外錯誤。

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