β-咔啉是一种天然生物碱，存在于动植物和微生物中，表现出广泛的生物学和药理学活性，如抗菌、抗肿瘤、抗病毒、抗疟疾、抗惊厥、抗血栓和中枢神经系统抑制活性等。咪唑并[1,2-a]吡啶化合物是有机化学中的重要中间体，广泛分布于天然产物和有机金属中，具有抗肿瘤、抗寄生虫、抗微生物、抗真菌、抗炎和催眠等生物活性，目前已应用于多种上市药物中。

本文基于药效拼接原理，对β-咔啉骨架进行修饰，在β-咔啉环1,2-位引入稠合咪唑结构，合成一系列新型β-咔啉衍生物，并从中筛选出抗肿瘤活性高的化合物，以期在癌症药物方面有所突破。

第一部分，以L-色氨酸和甲醛为原料，经过Pictet-Spengler反应、氧化、氨基取代和N⁹-烷基化等多步反应，生成中间体化合物9-取代-1-氨基-β-咔啉，再与不同的溴代酮反应，共合成40个2,11-二取代β-咔啉并咪唑衍生物。

第二部分，以前期合成的重要中间体化合物9-取代-1-氨基-β-咔啉为原料，与不同的醛进行反应，共合成29个3,11-二取代β-咔啉并咪唑衍生物。

以上两部分共合成69个化合物，化合物结构通过¹H NMR、¹³C NMR、HRMS和X单晶衍射进行确证，并采用MTT法，将化合物对肺癌（A549）、胃癌（BGC-823）、小鼠结肠癌（CT-26）、肝癌（Bel-7402）和乳腺癌（MCF-7）五种肿瘤细胞进行了体外抗肿瘤活性测试。结果表明，大部分化合物对肿瘤细胞具有一定的活性，部分化合物对一种或多种肿瘤细胞表现出高于阳性对照顺铂的抑制活性。

初步的构效关系分析表明，第一部分化合物中，在目标化合物骨架的C 2位引入4-氟苯基、4-三氟甲基苯基或4-甲氧基苯基，或在C 11位引入苄基或4-氟苄基，可提高化合物的抗肿瘤活性；C 2位为芳基取代基时，相比于烷基取代基活性有所提高。第二部分化合物中，在化合物骨架的C 3位引入4-氟苯基或4-甲氧基苯基，或在C 11位引入苄基或4-氟苄基，化合物的抗肿瘤活性有所提高；化合物抗肿瘤活性与C 11位取代基的关系：4-氟苄基>苄基>苯丙基>甲基>氢。此外，使用OpenEye软件对合成的化合物进行了分子对接模拟，并用PyMOL和Discovery Studio（DS）软件进行可视化分析。结果显示，目标化合物能够与靶标蛋白形成相对稳定的结合，并与蛋白质产生氢键等多种相互作用。

另外，将两部分目标化合物的活性进行了对比。对比两部分11-位取代基相同，2-、3-位取代基也相同的化合物，发现3-位取代基化合物活性整体高于2-位取代基化合物，其中化合物T9db对五种肿瘤细胞均表现出良好的抑制活性（IC₅₀值均低于10 μM），具有作为抗癌先导药物的潜力，丰富了β-咔啉衍生物数据库。

β-carboline is a natural alkaloid found in animals, plants, and microorganisms, exhibiting a wide range of biological and pharmacological activities such as antibacterial, anticancer, antiviral, antimalarial, anticonvulsant, anti-thrombotic, and central nervous system inhibitory activities. Imidazo[1,2-a]pyridine compounds serve as an important intermediates in organic chemistry, widely distributed in natural products and organometallics, possessing biological activities including anticancer, antiparasitic, antimicrobial, antifungal, anti-inflammatory, and sedative properties, and are currently utilized in various marketed drugs.

Based on the principle of pharmacophore grafting, this study modifies the β-carboline skeleton by introducing a fused imidazole structure at the 1,2-positions of the β-carboline ring, synthesizing a series of novel β-carboline derivatives. Among them, compounds with high anticancer activity are screened, aiming to make breakthroughs in cancer drug development.

In the first part, starting from L-tryptophan and formaldehyde, a series of reactions including Pictet-Spengler reaction, oxidation, amino substitution, and N⁹-alkylation were carried out to generate the intermediate compound 9-substituted-1-amino-β-carboline. Subsequently, this intermediate compound was reacted with various bromoketones to synthesize a total of 40 2,11-disubstituted β-carboline fused imidazole derivatives.

In the second part, utilizing the previously synthesized crucial intermediate compound, 9-substituted-1-amino-β-carboline, as a starting material, it undergoes reactions with various aldehydes, leading to the synthesis of 29 3,11-disubstituted β-carboline fused imidazole derivatives.

The two parts combined synthesized a total of 69 compounds. The structures of these compounds were characterized via ¹H NMR, ¹³C NMR, HRMS, and X-ray single crystal diffraction. Furthermore, the anti-tumor activities of these compounds were evaluated in vitro using the MTT assay against five types of tumor cells: lung cancer (A549), gastric cancer (BGC-823), murine colon cancer (CT-26), liver cancer (Bel-7402), and breast cancer (MCF-7). The results indicate that most compounds exhibit certain activities against tumor cells, with some compounds showing inhibitory activity against one or more types of tumor cells surpassing that of the positive control, cisplatin.

Preliminary structure-activity relationship (SAR) analysis indicates that in the compounds synthesized in the first part, introducing 4-fluorophenyl, 4-trifluoromethylphenyl, or 4-methoxyphenyl at the C2 position of the target compound skeleton, or introducing benzyl or 4-fluorobenzyl at the C11 position, can enhance the anti-tumor activity of the compounds. When the C2 position is substituted with an aryl group, the activity is higher compared to alkyl substitution. In the compounds synthesized in the second part, introducing 4-fluorophenyl or 4-methoxyphenyl at the C3 position of the compound skeleton, or introducing benzyl or 4-fluorobenzyl at the C11 position, leads to an increase in the anti-tumor activity of the compounds. The relationship between the anti-tumor activity of the compounds and the substituents at the C11 position is as follows: 4-fluorobenzyl > benzy l> phenethyl > methyl > hydrogen. Additionally, molecular docking simulations of synthesized compounds were performed using OpenEye software, followed by visual analysis with PyMOL and Discovery Studio (DS) software. The results indicate that the target compounds can form relatively stable binding with the target protein, engaging in various interactions such as hydrogen bonding with the protein.

Furthermore, the activities of the target compounds from both parts were compared. By comparing compounds with identical 11-position substituents and identical 2- and 3-position substituents, it was observed that compounds with 3-position substituents exhibited overall higher activity than those with 2-position substituents. Specifically, compound T9db demonstrated potent inhibitory activity against five types of tumor cells (IC₅₀ values all below 10 μM), indicating its potential as a lead anti-cancer agent and enriching the database of β-carboline derivatives.

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