编者按：在新药研发的版图上，大环分子正以其独特的环状骨架，在小分子与生物药之间开辟出一条新路径，打破 " 难以成药 " 的边界。然而，大环分子合成路径复杂，长期制约着该类药物的研发效率。为应对这类行业挑战，药明康德多年来持续耕耘，构建了一套系统化解决方案。药明康德研发化学服务部目前已汇聚了 20 余种代表性的环化方法，形成系统的技术工具箱，可灵活应对各类分子结构挑战，显著提升合成效率和成功率。从分子设计、合成优化到放大制备，团队不断夯实一体化能力，助力合作伙伴将复杂的大环化合物高效转化为可行的药物候选分子。

几年前，药明康德研发化学服务部（Research Chemistry Services，RCS）接到了一项新任务：为某客户项目合成一个大环内酯类化合物。项目初期，客户提供的路线虽能拿到目标分子，但反应复杂，主要副产物二聚体占比高，目标产物收率仅约 13%。更棘手的是，产物与副产物极性相近，纯化效率低，放大更是困难。对于一款正向临床推进关键阶段的分子而言，这条路线远不能满足从克级到百克级乃至更大规模的供应需求。

接手后，RCS 团队基于对大环反应机理的深刻理解和丰富项目积淀，系统剖析副产物生成路径，并开展持续条件优化。经多轮优化筛选，团队锁定关键的反应参数组合，显著提升主产物选择性，使原先复杂的反应体系变得清晰可控。纯化步骤随之简化，收率从 13% 跃升至 45%。

收率的突破只是开端，真正的考验在于放大可行性。依托团队在大环化学领域的深厚功底，最终成功实现了 80 克级以上目标化合物的稳定制备。

这并非偶然，而是药明康德在大环化学领域十余年持续深耕的缩影。经过多年发展，团队不仅具备攻克复杂合成难题的能力，更依托一体化平台，为大环工艺的可放大性与高效交付奠定了坚实根基。

图片来源：123RF

大环类药物持续进化

故事要从大环分子的独特之处讲起。

大环分子通常指由至少 12 个重原子（即除氢以外的原子）构成的环状骨架。历史上，大环类药物最初来源于天然产物，红霉素、利福霉素、环孢素 A 等经典药物皆属此列。天然骨架为药物化学家提供了最初的灵感，但在尝试通过化学合成拓展新的大环化学空间时，却长期受制于一个核心瓶颈：关环效率极低。

转折发生在世纪之交。2005 年，烯烃复分解反应（RCM）荣获诺贝尔化学奖，该技术通过金属催化剂实现了碳 - 碳双键的交换与重组，使以往步骤冗长、收率低下的大环化反应变得切实可行。这一技术迅速在药物合成领域释放出巨大价值：全球多款获批上市的丙型肝炎病毒（HCV）蛋白酶抑制剂，其关键大环骨架正是通过 RCM 构建。不仅如此，这项技术还广泛地赋能于抗病毒药物、抗癌药物及免疫抑制剂等多个治疗领域的大环核心结构的构建，成为一条高效且稳健可靠的技术路径。

根据 2026 年 2 月《药物化学杂志》（J. Med. Chem.）发表的社论统计，美国 FDA 已批准超过 60 个大环药物，广泛覆盖感染、肿瘤、自身免疫性疾病等领域，代表性药物包括治疗丙肝的 NS3/4A 蛋白酶抑制剂、治疗肥胖症的黑皮质素 -4 受体激动剂、治疗骨髓纤维化的 JAK2 抑制剂以及治疗非小细胞肺癌的 ROS1/TRK 抑制剂等。

这一数字约占 FDA 全部获批药物（不含生物制品）的 4%。受限于合成难度，大环化合物的开发程度仍相对有限。

近年来，除了烯烃复分解反应之外，分子内 C – H 芳基化、模板环化等新兴策略不断涌现，正大幅简化大环药物的合成路线设计。合成技术的持续突破，叠加新靶点研发需求的驱动，共同推动大环化合物重返产业视野。

更深层的意义在于，大环分子正成为当下攻克 " 不可成药靶点 " 的关键角色之一。研究表明，从分泌蛋白、细胞表面受体到缺乏可成药结合口袋的细胞内蛋白，大环分子均能实现有效结合。其分子量介于小分子与生物制品之间（约 500 – 2000 Da），在功能上兼具二者之长：既能达成小分子难以企及的高亲和力，并有潜力克服生物制品难以触达胞内靶点的限制。今年 2 月 J. Med. Chem. 的一篇报道将这一特性形象地概括为—— " 分子外交官 "。

这种独特的功能整合，根植于大环分子环状骨架的构象可塑性。它能根据周围环境的极性差异，选择性采用不同的优势构象——在水性环境中暴露极性基团以维持溶解性，在疏水的膜环境中则通过分子内氢键屏蔽极性，从而利于跨膜运转。这一特性，也使其被业内形象地称为 " 分子变色龙 "。

正是这种特质，赋予大环分子在口服给药领域的独特潜力——既具备突破透膜屏障的能力，又能维持良好的全身暴露水平，不断拓展传统口服药物设计的边界。同时，这种灵活的环境响应性还赋予其极高的结合亲和力，部分经优化的分子可达到纳摩尔甚至亚纳摩尔级别，与抗体相当。

尽管前景广阔，但挑战亦存。大环药物研发的核心挑战之一，仍集中在合成环节：关环效率低、路线冗长、放大生产难度高，这些问题共同制约着此类药物的开发进度。合成一个结构精巧的大环分子，无异于在微观尺度上完成一场精密的 " 首尾相接 "。这不仅要求对反应机理的深刻理解，更依赖工艺化学等多学科团队的紧密协作。唯有如此，才能将这些 " 美丽而任性 " 的分子，从文献里的结构式转化为真正惠及患者的疗法。

十多年深耕，构筑大环化学能力体系

面对大环合成这一行业挑战，药明康德通过十多年持续积累，已构建起系统性的解决方案。药明康德 RCS 团队围绕大环合成中的关键瓶颈，建立了 20 余种代表性关环方法的技术工具箱，能够根据分子结构特征灵活选择更优合成策略，有效提升合成的成功率与效率。与此同时，团队持续打磨从分子设计、合成优化到可放大制备的一体化能力，助力合作伙伴高效地将复杂分子转化为具备开发潜力的候选药物。

截至目前，药明康德 RCS 团队已成功合成超过 1 万个大环化合物，结构类型涵盖大环内酯、内酰胺、磺酰胺 / 磺酰亚胺、环醚等多样化骨架，并在复杂合成路线的稳定放大中积累了扎实的实操经验。

在药明康德一体化平台的加持下，团队还将流动化学技术引入大环类化合物的放大生产环节，为客户提供更稳定、高效的放大工艺路径，从而更好、更快地推进项目。

这套针对大环化合物的一体化能力体系，已在抗感染、免疫、肿瘤等多个治疗领域的药物研发中展现赋能价值。以某抗感染项目为例，客户需要短期内快速交付一系列结构多样的大环类似物用于构效关系研究。药明康德 RCS 团队通过优化路线设计，借助高效率的关环方法，按时高质量交付全部化合物，显著缩短了客户的药物发现周期。

在另一客户项目中，目标大环分子的合成同样面临关环挑战。文献报道的现有酯化关环策略在这一项目中效果不佳，主要生成二聚副产物，目标产物几不可得。面对这一僵局，RCS 团队并未止步于既有方法，而是从分子结构和反应机理出发深入研判，最终果断将合成路线转向偶联反应，成功实现了目标大环的高收率制备。

技术演进与行业需求从未止步，大环化学的边界也在不断拓展。例如，如何通过催化手段高效构建手性大环，正成为前沿关注的热点。今年 2 月，《科学》（Science）杂志报道了一项技术突破：研究团队基于 2021 年诺贝尔化学奖所表彰的不对称有机催化理论，利用双功能肽催化剂，对线性前体的末端功能基团进行模板化，成功合成了天然产物 robotnikinin 的核心结构。这一策略为立体化学可预测的手性大环合成提供了一条可行路径，亦彰显了不对称催化在大环构建中的独特优势。

与此同时，科学界正将目光投向结构更复杂、靶向性更明确的新型分子，大环分子正是其中的典型代表。随着合成方法的持续革新、药化认知日益深入、前沿技术加速涌现，大环分子有望在新药研发中扮演愈发重要的角色。

作为医药创新的赋能者，药明康德始终跟随科学、跟随客户需求，持续建设并迭代大环化学领域的技术和能力。同时，公司也将持续夯实包括大环分子在内的各类复杂分子的能力建设，更好地为行业和客户提供赋能支持，助力全球客户加速将新药、好药带给需要的患者。

这些努力，归根结底，是药明康德对 " 让天下没有难做的药，难治的病 " 这一愿景的坚定实践——让难以成药的靶点有机会被攻克，让复杂分子的合成有径可循，让全球创新者拥有更高效的新药研发路径，最终让更多创新疗法惠及患者。

How WuXi AppTec Helps Clients Overcome Macrocycle Synthesis Challenges?

To address the industry-wide challenge of macrocycle synthesis, WuXi AppTec has developed a systematic solution through years of continuous effort. The team has assembled a technical toolbox of over 20 representative cyclization methods to address the key hurdles in macrocycle synthesis, enabling flexible selection of the optimal synthetic route based on molecular structural characteristics, and thereby effectively improving synthesis success rates and overall efficiency. Meanwhile, the team continuously refines its integrated capabilities — from molecular design and synthesis optimization to scalable preparation, helping partners efficiently transform complex macrocyclic compounds into viable drug candidates.

Several years ago, WuXi AppTec ’ s Research Chemistry Services ( RCS ) team took on a new assignment. A client project required the construction of a macrolide compound. In the project ’ s early phase, the route provided by the client was able to construct the target molecule, but the reaction was complex, and the main byproduct — a dimer — accounted for a significant fraction of the product mixture, resulting in an isolated yield of just 13% of the desired product. To compound the issue, the product and byproduct had similar polarity, making purification inefficient and scale-up even more difficult. For a molecule at a critical stage of clinical advancement, this synthesis clearly could not meet the supply requirements as the program progressed from gram-scale to hundred-gram batches and beyond.

Upon taking over the project, the RCS team analyzed the byproduct formation pathway based on their mechanistic understanding and extensive project experience, and systematically optimized the reaction conditions.   Through multiple rounds of design and screening, they identified key parameter combinations that significantly improved selectivity for the desired product. What was once a complex reaction system became well-controlled and predictable. Purification steps were simplified, and the yield was boosted from 13% to 45%.

The yield improvement was only the first step. Scale-up presented an even greater challenge to the team ’ s process development capabilities. Leveraging their deep expertise in macrocycle chemistry, the team successfully achieved reproducible synthesis of the target macrocycle at a scale exceeding 80 grams.

This case is underpinned by years of accumulated expertise in macrocycle chemistry at WuXi AppTec. Today, the team combines the ability to solve complex macrocycle synthesis challenges with a solid foundation for scalable process development — built upon its integrated platform.

Image source: 123RF

Macrocyclic Drugs: Breaking the "Undruggable" Barrier, but Synthesis Remains Daunting

Macrocycles are generally defined as organic molecules containing a ring of at least 12 heavy atoms ( atoms other than hydrogen ) . Historically, macrocyclic drugs originated from natural sources, with classic examples including erythromycin, rifamycin, and cyclosporine A.   Inspired by these natural frameworks, medicinal chemists have attempted to explore new macrocyclic chemical space through chemical synthesis, but have long been constrained by a core challenge: notably low cyclization efficiency.

A milestone breakthrough occurred at the beginning of this century.   In 2005, olefin metathesis, particularly ring-closing metathesis ( RCM ) was recognized with the Nobel Prize in Chemistry. This technology enables the exchange and rearrangement of carbon – carbon double bonds through metal catalysts, making previously multi-step, low-yield macrocyclization reactions more feasible.   This technology quickly demonstrated its value in drug synthesis: the key macrocyclic scaffolds of several FDA-approved hepatitis C virus ( HCV ) protease inhibitors were constructed via RCM. Moreover, it provides an efficient and reliable technical pathway for building the core structures of various macrocyclic drugs, including antiviral agents, anticancer drugs, and immunosuppressants.

According to an editorial in the   Journal of Medicinal Chemistry   ( February 2026 ) , the   FDA has approved more than 60 macrocyclic drugs for indications including infectious diseases, oncology, and autoimmune disorders.   These include NS3/4A protease inhibitors for hepatitis C, melanocortin-4 receptor inhibitors for obesity, JAK2 inhibitors for myelofibrosis, and ROS1/TRK inhibitors for non-small cell lung cancer.

This number represents approximately 4% of all FDA-approved drugs ( excluding biologics ) . Due to the inherent difficulty of synthesizing macrocycles, they have historically been underdeveloped as a drug class.

In recent years, beyond RCM, emerging methods such as intramolecular C – H arylation and template-directed cyclization have been continuously streamlining the design of synthetic routes for macrocyclic drugs. These ongoing innovations in synthetic technology, combined with growing R&D demand for novel targets, are driving a resurgence of industry interest in macrocyclic drugs.

More importantly,   macrocyclic drugs are emerging as key players in tackling historically "undruggable" targets.   Studies show that macrocycles can effectively bind to secreted proteins, cell surface receptors, and intracellular proteins lacking druggable binding pockets. With molecular weights that fall between those of small molecules and biologics ( roughly 500 – 2000 Da ) , they functionally combine the advantages of both: achieving high binding affinity that small molecules often cannot, while overcoming the inability of biologics to reach intracellular targets. A February 2026 report in the   Journal of Medicinal Chemistry   vividly described macrocycles as "molecular diplomats."

The ability of macrocycles to integrate the advantages of small molecules and biologics stems from their unique cyclic scaffold. They can selectively adopt different dominant conformations depending on the polarity of their environment — exposing polar groups in aqueous environments to maintain solubility, and shielding polarity through intramolecular hydrogen bonds in hydrophobic membrane environments to facilitate transmembrane transport. For this reason, they are also colloquially called "molecular chameleons."

This characteristic gives macrocycles unique potential in oral drug delivery — they can simultaneously breach membrane barriers and maintain systemic exposure, expanding the boundaries of traditional oral drug design. Moreover, this environment-responsive property also endows macrocycles with high binding affinity, with some optimized molecules achieving nanomolar to sub-nanomolar potencies, comparable to those of antibodies.

Despite these promising prospects, the development of macrocyclic drugs is not without significant challenges.   One core challenge lies in synthesis: low cyclization efficiency, lengthy synthetic routes, and scale-up difficulties — factors that collectively limit the pace of advancement for such molecules.

WuXi AppTec ’ s Integrated Platform Addresses Macrocyclic Drug Synthesis Challenges

WuXi AppTec ’ s RCS team has built a mature macrocycle chemistry capability, drawing on years of experience in macrocyclic drug research to provide partners with integrated support — from molecular design and synthesis optimization to scalable preparation.  

To address challenges such as low cyclization efficiency, complex conformational control, and scale-up difficulties in macrocycle synthesis, WuXi AppTec has assembled a technical toolbox of over 20 representative cyclization methods. These include Mitsunobu cyclization, RCM cyclization, lactam cyclization, sulfonamide cyclization, click reaction, reductive amination, C – H activation, and disulfide bond formation. This allows the team to flexibly select the optimal route based on the molecular characteristics of each target, improving synthesis success rates and overall efficiency. This capability works in deep synergy with the company ’ s integrated platform, helping customers efficiently advance complex molecules into drug candidates with real development potential.

To date, the WuXi AppTec RCS team has synthesized over 10,000 macrocyclic compounds, covering structural classes such as macrolides, lactams, sulfonamides/sulfonimides, and cyclic ethers. The team has accumulated solid hands-on experience in the reproducible scale-up of complex synthetic routes.

Leveraging WuXi AppTec ’ s integrated platform, the team has also applied flow chemistry to the scale-up production of macrocyclic compounds, providing clients with a more stable and efficient scale-up pathway to better enable the advancement of their projects.

This integrated technical system for macrocyclic compounds has demonstrated its enabling value in drug research projects across fields including anti-infectives, immunology, and oncology. Consider an anti-infective program: in response to a client ’ s SAR ( structure – activity relationship ) study requirements, the RCS team optimized the synthetic route and, leveraging efficient cyclization methods, rapidly delivered a range of structurally diverse macrocycle analogs, helping the client accelerate the drug discovery timeline.

In another client project, the synthesis of the target macrocycle faced cyclization challenges. The existing esterification cyclization strategy reported in the literature proved ineffective for this project, mainly generating dimer byproducts and failing to yield the desired product. Rather than defaulting to existing methods, the RCS team conducted an in-depth analysis of the molecular structure and reaction mechanism. Ultimately, they re ‑ routed the synthetic strategy toward a coupling reaction, successfully achieving high-yielding synthesis of the target macrocycle.

Currently, both technological development and industry demands continue to evolve, the boundaries of macrocycle chemistry are constantly expanding. For example, how to efficiently introduce chirality into macrocycles via catalytic methods remains a frontier question in the field. In February 2026, the journal   Science   reported a technological breakthrough: building on the asymmetric organocatalysis principles recognized by the 2021 Nobel Prize in Chemistry, a research team used bifunctional peptide catalysts to pre-organize the terminal functional groups of linear precursors, successfully synthesizing the core structure of the natural product robotnikinin.   This method provides a practical route to chiral macrocycles with predictable stereochemistry, highlighting the critical role of asymmetric catalysis in such syntheses.

At the same time, drug discovery is increasingly guiding the industry toward frontier molecules with more complex structures and better-defined targeting; macrocycles are a prime example. With innovations in synthetic methods, a deeper understanding of medicinal chemistry, and the rapid emergence of cutting-edge technologies, macrocyclic molecules are poised to play an increasingly important role in future therapeutic development.  

As an enabler of innovation, WuXi AppTec stays attuned to both scientific progress and client needs, continuously expanding and refining its capabilities and technologies in macrocycle chemistry. Alongside this, the company will continue to strengthen its capabilities across various complex molecule modalities, including macrocycles, to better serve the industry and its clients, helping global clients accelerate the delivery of new and better medicines to patients in need.

Key Takeaways:  

To address challenges such as low cyclization efficiency, complex conformational control, and scale-up difficulties in macrocycle synthesis, WuXi AppTec RCS has assembled a technical toolbox of over 20 representative cyclization methods. These include Mitsunobu cyclization, RCM, lactam cyclization, sulfonamide cyclization, click reaction, reductive amination, C – H activation, and disulfide bond formation. This allows the team to flexibly select the optimal route based on the molecular characteristics of each target, improving synthesis success rates and overall efficiency.

WuXi AppTec's capability of macrocycle synthesis works in close synergy with the company ’ s integrated platform, enabling projects to strike a balance between innovative design and process feasibility early in development, and helping partners efficiently advance complex molecules into drug candidates with real development potential.

Leveraging WuXi AppTec ’ s integrated platform, the WuXi AppTec RCS team has also applied flow chemistry into the scale-up production of macrocyclic compounds, providing clients with a more stable and efficient scale-up pathway to better enable the advancement of their projects.