CN116425830A - 一种具有抗癌活性的小分子肽及其应用 - Google Patents
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Abstract
本发明涉及药物化学领域，涉及一种具有抗癌活性的小分子肽及其应用。通过生物信息平台对红串红球菌D‑1的基因组进行挖掘，发现了新结构的NRPS基因簇，预测出该NRPS合成的非核糖体肽的可能的分子结构，并通过化学合成得到一个小分子肽，经检测，其表现出一定铁载体活性测定，可以抑制人结肠癌HCT116细胞的增值，有新型抗癌药物开发的价值。
Description
技术领域
本发明涉及药物化学领域，涉及一种具有抗癌活性的小分子肽，以及其在制备抑制人结肠癌HCT116细胞增值的药物中的应用。
背景技术
肿瘤对人类健康有着巨大威胁，迄今为止依然是对人类危害最大的高死亡疾病之一，因此发现高效优质的新抗癌药物成为全世界的重要研究课题。非核糖体肽是微生物的次级代谢产物，由非核糖体肽合成酶(NRPS,Nonribosomal Peptide Synthase)合成，结构多样，是天然产物的重要来源之一。在临床领域被广泛应用，如万古霉素、青霉素、博来霉素和放线菌素等。然而，菌株中的大量合成基因簇在实验室常规培养条件下大多是沉默的或表达量很低，很难通过分离得到相应非核糖体肽；另外激活这些沉默基因簇需要针对不同的菌株进行大量的分子遗传学工作，过程繁琐、周期长、费用高，在筛选菌株、分离纯化和表征合成路径等过程中需要耗费大量的时间、精力和金钱。
随着对天然产物合成酶的结构与功能关系的不断深入研究，生物信息学家开发出了一些软件(如antiSMASH等)，根据合成酶的结构来预测其产物，研究者将这些软件的预测结果与化学合成手段结合起来，开发出一种新的发掘天然产物的途径，即合成-生信天然产物(synthetic-bioinformatic natural product，syn-BNP)法。通过生物信息学对基因簇一级序列进行分析，预测化合物的潜在化学结构，然后通过化学合成产生合成预测产物。
本发明对一株红串红球菌D-1进行全基因组测序后，将测序结果导入生物信息数据库进行分析。通过antiSMASH5.0数据库预测出一个红串红球菌NRPS合成的非核糖体肽的可能的分子结构，再经化学合成得到了这些小分子肽，最后进行活性表征，发现其中一个小分子肽对结肠癌细胞的增值具有抑制效果。
发明内容
为加速天然产物的挖掘和丰富天然产物分子库，本发明使用软件预测出一株红串红球菌基因组中一个NRPS合成的非核糖体肽的可能的分子结构，再通过化学合成得到了这些小分子肽，经检测其中一个小分子肽对结肠癌细胞的增值具有抑制效果。
一种具有抗癌活性的小分子肽，化学式为C21H38N4O7(化合物1)，结构式如下：
所述具有抗癌活性的小分子肽可应用于制备抗癌药物。
所述小分子肽对结肠癌细胞的增值具有抑制效果。
本发明的有益效果：
本发明通过对一株红球菌基因簇的挖掘得到了一个小分子肽。对该化合物进行抗癌实验发现，其对结肠癌细胞的增值具有抑制效果。因此，该化合物有望成为抗癌药物的先导化合物并具有良好的开发前景。
附图说明
图1是本发明实施例中抗癌化合物正离子质谱图
图2是本发明实施例中抗癌化合物HPLC谱图
图3是本发明小分子肽铁载体活性结果图
图4是本发明小分子肽对HCT116细胞的抗癌活性结果图
具体实施方式
本发明结合附图和实施例作进一步的说明。实施例中所使用的细胞培养基成分：DMEM培养液，使用前每500ml DMEM加入5ml的L-谷氨酰胺和青霉素-链霉素双抗，再加25ml的胎牛血清。在37℃、5％二氧化碳浓度条件下培养细胞。
本发明的小分子肽根据其结构式可以直接通过全化学合成多肽技术制得，本实施例仅提供其一种具体合成思路作为说明，并非对其的限制：从固相树脂上从C端开始三个氨基酸逐一接上去，依次是Fmoc-Orn(Boc)-OH,Fmoc-Gly-OH,Fmoc-D-Asp(OtBu)-OH,最后脱掉Fmoc保护基团，接上癸酸，然后用TFA把多肽从树脂上切下来并同时去除侧链保护。得到的多肽粗品经过HPLC纯化，然后冻干。
成品经过了HPLC分析纯度和MS确认分子量。
所得产物的正离子质谱及HPLC谱图如图1、2所示，本实例中将该小分子肽命名为ZJURENRP1-FA，简称1-FA。该小分子肽具有抑制HCT116细胞增殖的作用，是一种具有应用前景的抗癌化合物。
(一)化合物的结构分析
本发明抗癌化合物为白色固体，易溶于二甲基亚砜，甲醇、微溶于水。
ESI-MS m/e 458.52([M+H]+)。
(二)铁载体活性检测
采用CAS检测法进行检测，原理是CTAB、络天青S和三价铁离子结合形成蓝色化合物，当铁载体遇到这个蓝色化合物时，由于铁载体对三价铁离子的亲和力更高抢走铁离子，导致溶液颜色由蓝色转变为橙黄色或红色。1-FA的铁载体活性如图3所示。水杨酸作为阳性对照，可以看到水杨酸和蓝色溶液混合后，颜色发生了显著变化变成红色，与CK组(在CAS检测液中加入DMSO)加入1-FA的检测液颜色发生了变化，从蓝色变成了浅红色，说明1-FA具有铁载体活性。
(三)抗癌活性检测
1、供试癌细胞
HCT116
2、抑癌活性的测定
抑癌活性采用MTT法。按照细胞传代步骤，消化细胞制成细胞悬浮液，以100μL6000个细胞铺在96孔板中，过夜培养。加入浓度梯度的1-FA，每孔100μL，设置三个重复，37℃培养48h。弃去孔内培养液，每孔加入50μL MTT(1mg/ml)，37℃避光孵育3h，再向每孔加入150μL DMSO处理30分钟。紫色结晶体彻底溶解后，通过酶标仪检测各孔570nm处的吸光值。
实验结果如图4所示，可以看出，相对于CK组(不加入1-FA培养细胞24h)，加入本发明的小分子肽化合物的实验组中结肠癌细胞HCT116数量明显降低，由此可知，该化合物对结肠癌细胞的增值具有抑制效果，有望将其应用于抗癌药物的制备中。
本发明的内容不限于具体实施方式所列举，本领域普通技术人员通过阅读本发明说明书而对本发明技术方案采取的任何等效的变换，均为本发明的权利要求所涵盖。
Claims (5)
1.一种具于抗癌活性的小分子肽，其化学式为C21H38N4O7，结构式如下：
2.如权利要求1所述的小分子肽的应用，其特征在于：所述化合物应用于制备抗癌药物。
3.如权利要求2所述的小分子肽的应用，其特征在于：所述的抗癌药物具有抑制人结肠癌HCT116细胞的增值的作用。
4.一种抑癌药，其特征在于，含有如权利要求1所述的小分子肽。
5.如权利要求4所述的抑癌药，其特征在于，所述抑癌药具有抑制人结肠癌HCT116细胞的增值的作用。
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| WO1988001173A1 (en) * | 1986-08-21 | 1988-02-25 | The Mount Sinai School Of Medicine | Benzylthioether-linked solid support-bound thiol compounds and method for peptide synthesis |
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