新型3-芳基异吲哚酮化合物的设计、合成与抗癌活性研究
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摘要
本论文共分为三章。在前期工作中发现的抗癌活性苗头化合物CDS-1548基础上，设计并合成了一系列3-芳基异吲哚酮化合物及其类似物，从而对苗头化合物进行较为系统的结构优化。之后对活性化合物进行初步的抗癌作用机制及手性-活性研究，确定了活性单体的绝对够型。
第一章介绍了背景材料及前期工作基础，引出了本论文的目的及意义。
当今社会，癌症是导致人类死亡的主要原因之一。而现有的抗癌药物仍存在对实体瘤疗效不理想，严重副作用，因患者基因的多样性和用药后产生的耐药性，而呈现明显疗效和毒性个体差异等不足。因此研发结构多样、高效低毒的新型抗癌药物以用于癌症的治疗势在必行。而针对癌细胞无限增殖、抵抗凋亡的特征，通过靶向于细胞周期或细胞凋亡通路中调控因子，从而诱导癌细胞发生细胞周期阻滞或细胞凋亡，从而治疗癌症的策略是行之有效的。
所有药物均具备有效、安全、质量可控三大基本要素，而手性药物因其不同手性异构体在活性、代谢及毒性等方面存在显著差异，被提出了更严格的要求。因此在研发过程中，阐明不同异构体的活性差异，有目的地设计和开发单一对映体是很有必要的。
异吲哚酮作为一类母核结构，广泛出现在众多活性化合物和药物结构中。在异吲哚酮3-位引入取代基后，可提高其体内代谢稳定性，且手性中心的引入有可能提高化合物的生物活性或降低毒副作用。鉴于3-取代异吲哚酮具有的结构优势，本实验室在前期工作中，设计、合成并发现了对癌细胞生长具有较好抑制活性的苗头化合物CDS-1548，其具有3-芳基异吲哚酮母核结构，IC_(50)=6.5μM (HeLa,48h)。
本论文是在前期工作基础上，通过对苗头化合物CDS-1548进行系统的结构优化，初步作用机制探索，以及手性活性研究，从而为更加深入的构效关系及化学生物学研究提供参考，并为此类结构抗癌先导化合物，乃至抗癌药物的发现奠定基础。
第二章介绍了苗头化合物CDS-1548类似物的设计、合成与抗癌活性研究。
首先，我们进行了苗头化合物类似物的设计。我们将CDS-1548结构分为A、B、C、D四个部分，针对不同结构片段，设计了两大类化合物。第一类为一系列3-芳基异吲哚酮化合物，我们拟从三个方面对苗头化合物进行结构改造：1)去除A或C片段，消除4-甲氧基苯甘氨醇片段手性中心，简化分子结构；2)对A和B部分苯环的取代基进行变化；3)对C部分的羟甲基进行官能团转化。第二类化合物，是在第一类化合物结构优化基础上，对D部分异吲哚酮母核结构进行改造，设计一系列3-芳基异吲哚酮类似物。具体设计过程中，我们拟通过减少芳环数量、引入氢键受体/给体、延长脂肪链长度等方法，实现提高类药性、降低LogP、增加分子柔性的目的，以期通过结构优化，提高化合物活性。
其次，我们进行了苗头化合物类似物合成方法的探索。我们先对3-芳基异吲哚酮化合物的合成方法进行了文献总结。在此基础上，我们选取还原N-酰亚胺离子的方法，经条件优化，探索了两条构建3-芳基异吲哚酮母核结构的路线。路线一：通过芳香酮酸与伯胺或其盐酸盐缩合，生成半缩酮中间体，再通过乙酸催化生成N-酰亚胺离子中间体，氰基硼氢化钠还原，从而消除异吲哚酮3-位羟基得到目标产物。此方法虽然产率偏低，但可在异吲哚酮2-位N-上进行多种取代基变化，从而实现分子多样性。路线二：通过酮酸和β-氨基醇脱水缩合，及三氟化硼乙醚/三乙基硅烷参与的还原开环反应，两步合成一系列具有β-氨基醇结构片段的异吲哚酮化合物。此方法优点在于操作简便，反应产率较高，易于纯化，缺点在于产物结构单一。两条路线相互补充，为我们进行全面构效关系研究提够了保证。
最后，我们利用改进的两条合成路线，对所设计的化合物进行了合成，并在Hela细胞上，通过MTT法进行了活性筛选。在第一类三个系列的3-芳基异吲哚酮化合物中，我们发现了活性较好的化合物2-168a (IC_(50)=9.5μM)、CDS-3078(IC_(50)=3.6μM)和2-219a (IC_(50)=15μM)。在第二部分结构优化中，我们针对活性化合物2-168a中D部分的异吲哚酮母核进行变化，合成了一系列3-芳基异吲哚酮类似物。通过活性测试，我们发现了活性较好化合物2-245(IC_(50)=10μM)和2-249(IC_(50)=25.4μM)。根据以上活性结果，我们发现潜在作用靶点对化合物结构有较强的选择性：1）A、B片段苯环上的取代基和C片段中的羟甲基部分，引入空阻或电性不适合的取代基，均导致活性的消失；2）一系列活性化合物都具有特定的手性构型，与其差向异构体活性差异明显，且增强分子柔性或刚性，使得构型改变甚至消失则直接导致活性消失。因此我们猜测潜在活性靶点具有高度保守的空间结构。此外，我们发现了相对活性最佳化合物CDS-3078（IC_(50)=3.6μM, Hela,48h）。因此，针对CDS-3078，研究手性对活性的影响成为我们下一阶段的目标。
第三章介绍了苗头化合物CDS-1548及活性化合物CDS-3078的初步作用机制研究及CDS-3078的手性-活性研究。
首先，我们通过光学显微镜及细胞流式的方法，对CDS-1548和CDS-3078抗肿瘤机制进行初步研究，发现两者在<10μM水平均能将HeLa细胞周期阻滞在G2/M期，并能诱导其发生早期凋亡，且作用具有浓度依赖性。之后，我们选择活性更好的CDS-3078研究手性与活性关系。通过合成CDS-3078的4个异构体，并进行手性纯度检测及绝对构型表征后，我们通过对三种不同癌细胞系HeLa、A549和SW1116进行活性测试，发现只有(S,S)型异构体具有诱导多种癌细胞凋亡活性，具有较广的抗瘤谱。通过手性-活性的研究，进一步说明此类3-芳基异吲哚酮化合物作用靶点可能高度保守，具有较强的蛋白-小分子相互作用结构选择性。深入的作用机制研究仍在进行中。
This dissertation is divided into three chapters. In previous work, compoundCDS-1548was found to have anticancer activity through screening. Based on this hitcompound, a series of3-aryl isoindolinones and their analogues were designed andsynthesized for systematic structure optimization. After that, the preliminaryanticancer mechanism of active compounds was studied, and the absoluteconfiguration of the most active isomer was determined.
In the first chapter, the background and previous work were described, and thenthe content and meaning of this dissertation was drawn.
Today, cancer is a major cause of human death. There are still some drawbacksof existing anticancer drugs, including the poor activity against solid tumors, severeside effects, and the apparent individual differences of efficacy and toxicity, due to thegene diversity of patients and drug resistance. In this way, the development of novelanticancer drugs with diverse structures, efficiency and low toxicity is imperative.Characteristics of cancer cells include unlimited proliferation and resistance toapoptosis. Thus, targeting the regulatory factors of cell cycle and apoptosis pathwayto induce cancer cell cycle arrest and apoptosis, is considered as the efficient strategyfor cancer treatment.
All medicines have three basic elements: effective, safe, and quality controlled.There are more stringent requirements for chiral drugs, owing to the differences ofactivity, metabolism or toxicity for different chiral isomers. Therefore, during theresearch and development process, to clarify the activity of each isomer, and develop single enantiomer is necessary.
Isoindolinone as a pharmacophore, widely appear in active compounds. Thesubstituents on3-position of the isoindolinone ring system have shown improvedmetabolic stability, and the chiral center is possible to increase the biological activityor reduce the toxicity of active compound. In the previous work, an anticancer activitycompound CDS-1548(IC_(50)=6.5μM, HeLa,48h), with3-aryl isoindolinone scaffoldwas found though screening from the isoindolinone compounds, which were designedand synthesized on the basis of the reported active compound.
In this dissertation, based on previous work, the systematic optimization of hitcompound CDS-1548, preliminary mechanism, and chiral-activity relationship ofactive compound were carried out. This work provides reference for the more in-depthstructure-activity relationships study, and lay the foundation for the discovery of leadcompounds, even anticancer drug with novel3-aryl isoindolinone skeleton.
In the second chapter, the design, synthesis and anticancer activity studies of theanalogs of hit compound CDS-1548were described.
First of all, the design of the analogs of the hit compound was carried out. Thestructure of CDS-1548was divided into A, B, C, D four parts, and two classes ofcompounds were designed. The first class compounds are all3-aryl isoindolinones,and the structure optimization was carried out from three aspects:1) removing A or Cpart to eliminate the chiral center of the4-methoxy phenylethanol fragment, forsimplifying the molecular structure;2) changing the substituent on the benzene ring ofA and B parts;3) changing the hydroxymethyl fragment in C part for other functionalgroups. The second class of compounds, as the analogs of3-aryl isoindolinone withthe modification on isoindolinone skeleton, was designed on the basis of the screeningresult of the first class of compounds. In order to improve drug-likeness, lower LogPand increase the molecular flexibility, the derivatives of CDS-1548were designedreasonably, by way of reducing aromatic rings, introducing of hydrogen bondacceptor or donor and extending alkyl chain. Through the structure optimization, thebest active compound was expected to be found.
Secondly, the synthetic routes of the analogues of hit compound were developed. The synthetic methods of3-aryl isoindolinone reported in literatures weresummarized firstly. Based on this, two synthetic routes were developed to build the3-aryl isoindolinone skeleton via the reduction of N-acyliminium ion. Route one: ketoacid was condensed with different primary amine or its hydrochloride to give3-hydroxy-3-aryl isoindolinone intermediate, which was then reduced by cyanosodium borohydride in glacial acetic acid to afford the product. Although the yield ofthis method is low, the substituent on N-can be changed to achieve the moleculardiversity. Route two: the tricyclic γ-lactam was produced by condensation of keto acidwith aminoalcohol in good yield. Then, the diastereomers were synthesized via borontrifluoride ether induced ring-opening of tricyclic lactam substrates, and hydrideaddition of N-acyliminium ion with triethylsilane. The high yield, ease of operationand purification are the advantages of this method, while few types of N-functionalgroup is the limitation. The two routes complemented each other, and thestructure-activity relationship studies were ensured.
Finally, designed compounds were synthesized through the two improvedsynthetic routes, and then screened in Hela cells by MTT assay., From the three seriesof3-aryl isoindolinone compounds in the first class, active compounds2-168a (IC_(50)=9.5μM), CDS-3078(IC_(50)=3.6μM) and2-219a (IC_(50)=15μM) were founded. In thesecond class, on the basis of the structure of compound2-168a, isoindolinoneskeleton in D part was modified and a series of3-aryl isoindolinone analogs weresynthesized. Through the screening, active compounds2-245(IC_(50)=10μM) and2-249(IC_(50)=25.4μM) were founded. According to the above results, it suggested thatthe potential target might have a restriction on the structure of compound:1) For thesubstituent on benzene ring of A, B part, and the hydroxymethyl moiety in C part, ifsteric hindered or electrical property did not match, the activity of compound wouldbe disappeard;2) All the active compounds have special configuration, while theirisomers were all inactive. And the activity was lost when the configuration of theactive compound was changed or disappeared. Therefore, we guess that the potentialtarget has a highly conserved spatial structure. In addition, the best active compoundsCDS-3078(IC_(50)=3.6μM, HeLa,48h) was found. Therefore, the chiral-activity relationship of CDS-3078became the goal of the next phase of our studies.
In the third chapter, the study of the initial mechanism of active compoundsCDS-1548and CDS-3078, and chiral-active relationship of CDS-3078weredescribed.
First, through the analysis by optical microscopy and flow cytometry, it isindicated that CDS-1548and CDS-3078could both arrest cell cycle at the G2/Mphase, and induce the early apoptotic in HeLa cell at10μM, in aconcentration-dependent manner. Second, the more active compound CDS-3078waschosen for the study of chiral-activity relationship. After the synthesis, determinationof chiral purities and absolute configuration of the four isomers of CDS-3078, threedifferent tumor cell lines HeLa, A549and SW1116were chosen for activity screening.Only the (S, S)-isomer3-8was found to induce the apoptosis of three tumor cells,which indicated that3-8had a broad spectrum of anticancer activity. These resultsfurther showed that the potential target of this kind of3-aryl isoindolinones and theiranalogs might be highly conservative, and the protein-small molecule interactionsmight have strong structural selectivity. Further study of mechanism is still inprogress.
第一章介绍了背景材料及前期工作基础，引出了本论文的目的及意义。
当今社会，癌症是导致人类死亡的主要原因之一。而现有的抗癌药物仍存在对实体瘤疗效不理想，严重副作用，因患者基因的多样性和用药后产生的耐药性，而呈现明显疗效和毒性个体差异等不足。因此研发结构多样、高效低毒的新型抗癌药物以用于癌症的治疗势在必行。而针对癌细胞无限增殖、抵抗凋亡的特征，通过靶向于细胞周期或细胞凋亡通路中调控因子，从而诱导癌细胞发生细胞周期阻滞或细胞凋亡，从而治疗癌症的策略是行之有效的。
所有药物均具备有效、安全、质量可控三大基本要素，而手性药物因其不同手性异构体在活性、代谢及毒性等方面存在显著差异，被提出了更严格的要求。因此在研发过程中，阐明不同异构体的活性差异，有目的地设计和开发单一对映体是很有必要的。
异吲哚酮作为一类母核结构，广泛出现在众多活性化合物和药物结构中。在异吲哚酮3-位引入取代基后，可提高其体内代谢稳定性，且手性中心的引入有可能提高化合物的生物活性或降低毒副作用。鉴于3-取代异吲哚酮具有的结构优势，本实验室在前期工作中，设计、合成并发现了对癌细胞生长具有较好抑制活性的苗头化合物CDS-1548，其具有3-芳基异吲哚酮母核结构，IC_(50)=6.5μM (HeLa,48h)。
本论文是在前期工作基础上，通过对苗头化合物CDS-1548进行系统的结构优化，初步作用机制探索，以及手性活性研究，从而为更加深入的构效关系及化学生物学研究提供参考，并为此类结构抗癌先导化合物，乃至抗癌药物的发现奠定基础。
第二章介绍了苗头化合物CDS-1548类似物的设计、合成与抗癌活性研究。
首先，我们进行了苗头化合物类似物的设计。我们将CDS-1548结构分为A、B、C、D四个部分，针对不同结构片段，设计了两大类化合物。第一类为一系列3-芳基异吲哚酮化合物，我们拟从三个方面对苗头化合物进行结构改造：1)去除A或C片段，消除4-甲氧基苯甘氨醇片段手性中心，简化分子结构；2)对A和B部分苯环的取代基进行变化；3)对C部分的羟甲基进行官能团转化。第二类化合物，是在第一类化合物结构优化基础上，对D部分异吲哚酮母核结构进行改造，设计一系列3-芳基异吲哚酮类似物。具体设计过程中，我们拟通过减少芳环数量、引入氢键受体/给体、延长脂肪链长度等方法，实现提高类药性、降低LogP、增加分子柔性的目的，以期通过结构优化，提高化合物活性。
其次，我们进行了苗头化合物类似物合成方法的探索。我们先对3-芳基异吲哚酮化合物的合成方法进行了文献总结。在此基础上，我们选取还原N-酰亚胺离子的方法，经条件优化，探索了两条构建3-芳基异吲哚酮母核结构的路线。路线一：通过芳香酮酸与伯胺或其盐酸盐缩合，生成半缩酮中间体，再通过乙酸催化生成N-酰亚胺离子中间体，氰基硼氢化钠还原，从而消除异吲哚酮3-位羟基得到目标产物。此方法虽然产率偏低，但可在异吲哚酮2-位N-上进行多种取代基变化，从而实现分子多样性。路线二：通过酮酸和β-氨基醇脱水缩合，及三氟化硼乙醚/三乙基硅烷参与的还原开环反应，两步合成一系列具有β-氨基醇结构片段的异吲哚酮化合物。此方法优点在于操作简便，反应产率较高，易于纯化，缺点在于产物结构单一。两条路线相互补充，为我们进行全面构效关系研究提够了保证。
最后，我们利用改进的两条合成路线，对所设计的化合物进行了合成，并在Hela细胞上，通过MTT法进行了活性筛选。在第一类三个系列的3-芳基异吲哚酮化合物中，我们发现了活性较好的化合物2-168a (IC_(50)=9.5μM)、CDS-3078(IC_(50)=3.6μM)和2-219a (IC_(50)=15μM)。在第二部分结构优化中，我们针对活性化合物2-168a中D部分的异吲哚酮母核进行变化，合成了一系列3-芳基异吲哚酮类似物。通过活性测试，我们发现了活性较好化合物2-245(IC_(50)=10μM)和2-249(IC_(50)=25.4μM)。根据以上活性结果，我们发现潜在作用靶点对化合物结构有较强的选择性：1）A、B片段苯环上的取代基和C片段中的羟甲基部分，引入空阻或电性不适合的取代基，均导致活性的消失；2）一系列活性化合物都具有特定的手性构型，与其差向异构体活性差异明显，且增强分子柔性或刚性，使得构型改变甚至消失则直接导致活性消失。因此我们猜测潜在活性靶点具有高度保守的空间结构。此外，我们发现了相对活性最佳化合物CDS-3078（IC_(50)=3.6μM, Hela,48h）。因此，针对CDS-3078，研究手性对活性的影响成为我们下一阶段的目标。
第三章介绍了苗头化合物CDS-1548及活性化合物CDS-3078的初步作用机制研究及CDS-3078的手性-活性研究。
首先，我们通过光学显微镜及细胞流式的方法，对CDS-1548和CDS-3078抗肿瘤机制进行初步研究，发现两者在<10μM水平均能将HeLa细胞周期阻滞在G2/M期，并能诱导其发生早期凋亡，且作用具有浓度依赖性。之后，我们选择活性更好的CDS-3078研究手性与活性关系。通过合成CDS-3078的4个异构体，并进行手性纯度检测及绝对构型表征后，我们通过对三种不同癌细胞系HeLa、A549和SW1116进行活性测试，发现只有(S,S)型异构体具有诱导多种癌细胞凋亡活性，具有较广的抗瘤谱。通过手性-活性的研究，进一步说明此类3-芳基异吲哚酮化合物作用靶点可能高度保守，具有较强的蛋白-小分子相互作用结构选择性。深入的作用机制研究仍在进行中。
This dissertation is divided into three chapters. In previous work, compoundCDS-1548was found to have anticancer activity through screening. Based on this hitcompound, a series of3-aryl isoindolinones and their analogues were designed andsynthesized for systematic structure optimization. After that, the preliminaryanticancer mechanism of active compounds was studied, and the absoluteconfiguration of the most active isomer was determined.
In the first chapter, the background and previous work were described, and thenthe content and meaning of this dissertation was drawn.
Today, cancer is a major cause of human death. There are still some drawbacksof existing anticancer drugs, including the poor activity against solid tumors, severeside effects, and the apparent individual differences of efficacy and toxicity, due to thegene diversity of patients and drug resistance. In this way, the development of novelanticancer drugs with diverse structures, efficiency and low toxicity is imperative.Characteristics of cancer cells include unlimited proliferation and resistance toapoptosis. Thus, targeting the regulatory factors of cell cycle and apoptosis pathwayto induce cancer cell cycle arrest and apoptosis, is considered as the efficient strategyfor cancer treatment.
All medicines have three basic elements: effective, safe, and quality controlled.There are more stringent requirements for chiral drugs, owing to the differences ofactivity, metabolism or toxicity for different chiral isomers. Therefore, during theresearch and development process, to clarify the activity of each isomer, and develop single enantiomer is necessary.
Isoindolinone as a pharmacophore, widely appear in active compounds. Thesubstituents on3-position of the isoindolinone ring system have shown improvedmetabolic stability, and the chiral center is possible to increase the biological activityor reduce the toxicity of active compound. In the previous work, an anticancer activitycompound CDS-1548(IC_(50)=6.5μM, HeLa,48h), with3-aryl isoindolinone scaffoldwas found though screening from the isoindolinone compounds, which were designedand synthesized on the basis of the reported active compound.
In this dissertation, based on previous work, the systematic optimization of hitcompound CDS-1548, preliminary mechanism, and chiral-activity relationship ofactive compound were carried out. This work provides reference for the more in-depthstructure-activity relationships study, and lay the foundation for the discovery of leadcompounds, even anticancer drug with novel3-aryl isoindolinone skeleton.
In the second chapter, the design, synthesis and anticancer activity studies of theanalogs of hit compound CDS-1548were described.
First of all, the design of the analogs of the hit compound was carried out. Thestructure of CDS-1548was divided into A, B, C, D four parts, and two classes ofcompounds were designed. The first class compounds are all3-aryl isoindolinones,and the structure optimization was carried out from three aspects:1) removing A or Cpart to eliminate the chiral center of the4-methoxy phenylethanol fragment, forsimplifying the molecular structure;2) changing the substituent on the benzene ring ofA and B parts;3) changing the hydroxymethyl fragment in C part for other functionalgroups. The second class of compounds, as the analogs of3-aryl isoindolinone withthe modification on isoindolinone skeleton, was designed on the basis of the screeningresult of the first class of compounds. In order to improve drug-likeness, lower LogPand increase the molecular flexibility, the derivatives of CDS-1548were designedreasonably, by way of reducing aromatic rings, introducing of hydrogen bondacceptor or donor and extending alkyl chain. Through the structure optimization, thebest active compound was expected to be found.
Secondly, the synthetic routes of the analogues of hit compound were developed. The synthetic methods of3-aryl isoindolinone reported in literatures weresummarized firstly. Based on this, two synthetic routes were developed to build the3-aryl isoindolinone skeleton via the reduction of N-acyliminium ion. Route one: ketoacid was condensed with different primary amine or its hydrochloride to give3-hydroxy-3-aryl isoindolinone intermediate, which was then reduced by cyanosodium borohydride in glacial acetic acid to afford the product. Although the yield ofthis method is low, the substituent on N-can be changed to achieve the moleculardiversity. Route two: the tricyclic γ-lactam was produced by condensation of keto acidwith aminoalcohol in good yield. Then, the diastereomers were synthesized via borontrifluoride ether induced ring-opening of tricyclic lactam substrates, and hydrideaddition of N-acyliminium ion with triethylsilane. The high yield, ease of operationand purification are the advantages of this method, while few types of N-functionalgroup is the limitation. The two routes complemented each other, and thestructure-activity relationship studies were ensured.
Finally, designed compounds were synthesized through the two improvedsynthetic routes, and then screened in Hela cells by MTT assay., From the three seriesof3-aryl isoindolinone compounds in the first class, active compounds2-168a (IC_(50)=9.5μM), CDS-3078(IC_(50)=3.6μM) and2-219a (IC_(50)=15μM) were founded. In thesecond class, on the basis of the structure of compound2-168a, isoindolinoneskeleton in D part was modified and a series of3-aryl isoindolinone analogs weresynthesized. Through the screening, active compounds2-245(IC_(50)=10μM) and2-249(IC_(50)=25.4μM) were founded. According to the above results, it suggested thatthe potential target might have a restriction on the structure of compound:1) For thesubstituent on benzene ring of A, B part, and the hydroxymethyl moiety in C part, ifsteric hindered or electrical property did not match, the activity of compound wouldbe disappeard;2) All the active compounds have special configuration, while theirisomers were all inactive. And the activity was lost when the configuration of theactive compound was changed or disappeared. Therefore, we guess that the potentialtarget has a highly conserved spatial structure. In addition, the best active compoundsCDS-3078(IC_(50)=3.6μM, HeLa,48h) was found. Therefore, the chiral-activity relationship of CDS-3078became the goal of the next phase of our studies.
In the third chapter, the study of the initial mechanism of active compoundsCDS-1548and CDS-3078, and chiral-active relationship of CDS-3078weredescribed.
First, through the analysis by optical microscopy and flow cytometry, it isindicated that CDS-1548and CDS-3078could both arrest cell cycle at the G2/Mphase, and induce the early apoptotic in HeLa cell at10μM, in aconcentration-dependent manner. Second, the more active compound CDS-3078waschosen for the study of chiral-activity relationship. After the synthesis, determinationof chiral purities and absolute configuration of the four isomers of CDS-3078, threedifferent tumor cell lines HeLa, A549and SW1116were chosen for activity screening.Only the (S, S)-isomer3-8was found to induce the apoptosis of three tumor cells,which indicated that3-8had a broad spectrum of anticancer activity. These resultsfurther showed that the potential target of this kind of3-aryl isoindolinones and theiranalogs might be highly conservative, and the protein-small molecule interactionsmight have strong structural selectivity. Further study of mechanism is still inprogress.
引文
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