University of Groningen Substrate exploitation of multicomponent reactions toward diverse scaffolds and applications in medicinal chemistry Li, Jingyao

University of Groningen

Substrate exploitation of multicomponent reactions toward diverse scaffolds and applications

in medicinal chemistry

Li, Jingyao

10.33612/diss.150511881

IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite from it. Please check the document version below.

Document Version

Publisher's PDF, also known as Version of record

Publication date: 2021

Link to publication in University of Groningen/UMCG research database

Citation for published version (APA):

Li, J. (2021). Substrate exploitation of multicomponent reactions toward diverse scaffolds and applications in medicinal chemistry. University of Groningen. https://doi.org/10.33612/diss.150511881

Copyright

Other than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons).

Take-down policy

If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim.

Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons the number of authors shown on this cover page is limited to 10 maximum.

Contributions

Acknowledgements

Publications

Conferences

About the author

Appendices

C

In chapter 1, I synthesized all the compounds, analyzed the data and provided feedback on writing the manuscript and assisted in replying to the referees comments during the revision process. In chapter 2, I was the project leader, I performed the synthesis, analyzed the data and wrote the manuscript. In chapter 3, I was the project leader. I developed the methodology, performed the synthesis, supervised the project, analyzed the data and wrote the manuscript. My college Pravin Patil and Angel J. Ruiz-Moreno conducted the physicochemical properties comparison of the virtual libraries. Katarzyna Kurpiewska and Justyna Kalinowska-Tłuścik did the X-ray analysis of the crystalized compounds. In chapter 4, I was the project leader. I developed the methodology, performed the synthesis, analyzed the data and wrote the manuscript. In chapter 5, I wrote part of the manuscript (mainly “Ternary complexes and kinetics” part), gave suggestions for the troubleshooting and provided feedback on the manuscript preparation. In chapter 6, I was involved in the synthetic part, I synthesized most of the compounds, wrote part of the manuscript (mainly chemistry part and SAR part), revised the whole manuscript. My college Wenjia Wang conducted the bioativity evaluation and docking part.

Acknowledgements

205

A

A

Upon writing the final word of my thesis and reflecting on my Ph.D. journey of the last four years, I am filled with gratitude for having met and worked with such caring and brilliant people. The valued guidance, support, and assistance they offered helped me immeasurably with the completion of my study. Although our memorable experiences are impossible to capture in words, I would like to take this opportunity to acknowledge you all from the bottom of my heart.

First and foremost, I would like to express my sincere gratitude to my supervisor Prof. Alexander Dömling. Alex, thank you so much for allowing me to join the Drug Design lab. I still remember our first online interview before I came to the Netherlands – I was worried about my expression and my oral English, which was at the time unrefined and made me extremely nervous. Thankfully, your gentle and friendly words, as well as your great sense of humor, quickly relieved my nerves. From that moment I could foresee how cheerful and genial your lab would be, and this was precisely the case when I arrived. Your abundant knowledge of Chinese food surprised me; it is a pity that I could not cook "youtiao" and chicken feet to satisfy your appetite. What surprised me more though is your diligence in your position: you read and send on the latest publications as soon as they become accessible, even when they are released at midnight, and you are always reachable during weekends and holidays. We can easily talk things over with you in the lab or your office because your door is always open for us to ask for assistance or otherwise communicate with you. Our lab is fully equipped with the latest experimental apparatus, which makes our research efficient and convenient – this is all credited to you. Working in your lab is the most fortunate opportunity I have had in my academic life, and I will forever appreciate the immeasurable assistance and guidance you offered during my Ph.D.

I would like to express my thanks to my second promotor Prof. Tad Holak of Jagiellonian University in Poland. Even though we haven't been able to meet each other face to face, our collaborations have lasted from the first year of my Ph.D. until the very end. Thank you for your valuable support on my MDM2 PROTAC project, the yearly Ph.D. evaluation, and my thesis submission.

I would also like to thank Prof. Matthew Groves for the useful suggestions from the biology aspect and our collaborations with the IL-17 project. . I feel very lucky that your

office was on the same floor as our lab. You always bring your kindness and happiness to me when every time we meet, and your beautiful British English accent makes me feel like I’m talking to a British movie character.

In the meantime, I would like to thank the members of the reading committee, Prof. F.J. Dekker, Prof. P.H. Elsinga, and Prof. T.J.J. M

ü

Many thanks to our dear secretary Jolanda. I could not have enjoyed such a smooth Ph.D. life without your support and help with various administrative issues, conferences, stationeries and so many other affairs, such as sending compounds to the collaborators and sending my thesis to the committees. Thank you so much for being such a helpful person.

I would like to thank our lab managers: Andre and Robin. Andre, you are the first person I met in the lab and you had then the same kind and welcoming smile that you always wear. You give such insightful and valuable advice and you are always generous in passing on your experiences to others. Patience and responsibility are the two most essential qualities that I learned from you. Now that you have obtained your Ph.D. and started your new career, I wish you all the best and a bright future! Robin, you are the only manager that we have in the lab now. Thank you so mcuh for helping me translate my summary into Dutch. You are always on standby ready to save the lab from becoming a mess. Thank you for your dedication to maintaining the lab; without your effort in repairing diverse instruments, ordering the reagents, schedule the meetings and so much more, I doubt the lab could still run. Thank you so much!

My sincere gratitude to my initial daily supervisor Dr. Ajay chandgude. Ajay, you are not only the one who brought me into the MCR chemistry field, but also the one who taught me how to become a real scientist and how to manage my time effectively. You are always the first to come to the lab and the last to leave. I so greatly admire your diligence and the precision to which you work, and it has brought you great accomplishments and success. It has been such a great pleasure for me to work with and learn from you. I wish you happiness and a successful, fulfilling career next at Harvard University.

I would like to express my gratitude to precious friends in our lab.

Acknowledgements

207

A

efforts that you made with my graduation and defense. Your excellent sense of humor means it is always relaxing to talk with you. You have a broad knowledge of the latest news and internet events; you cater to all kinds of topics to pit everyone around you at ease. I wish you plenty of fine publications and a sweet life with Ruixue. Mojgan, my beautiful office mate, it has been a great pleasure to share an office with you. You are an expert on cooking and I love the Iranian snacks you bring in to share. You also have good taste in fashion and I love your outfits, especially the scarves you wear every day. You are like a bosom sister to me in our group, I cherish the talks that we had inside and outside the office. I wish you all the best with all your projects and a happy life with your husband.

Markella, Fandi, and Roberto, my oldest friend in the lab, many thanks for all the happy moments with you guys. Markella, , you are the most perfect Ph.D. researcher in my eyes. You are every bit as smart and erudite as Hermione Granger. Any time I came across some academic issue, I knew that I could easily find the answers at your place. Thank you for all your concern and assistance, and I wish you could also become a superstar like your sister Kristen Stewart in the academic field. Fandi, you are like an older brother to me in Groningen. You could always warm my heart with your kind and considerate words. Thank you for inviting me to your place for such delicious food, and I wish that you find a nice position at the university in your hometown and enjoy a sweet life with your wife. Roberto, you are always helpful and like a guardian for the lab. Even though you are not a lab manager you helped Robin with so much instrument maintenance from which we all benefitted. I enjoyed the time we attended a conference in Dusseldorf and smoked Hookah (is that how people call it?) together. Thank you for all your help, it is so exciting that you are going to have a new member of your family soon, so I hope that you are blessed with a beautiful and healthy baby.

Many thanks to our postdocs Shabnam and Patil. Shabnam, you are a beautiful Iran girl and a warm colleague to me. I know that you are going to another postdoc in Germany or the USA, I hope you have a lot of achievements in your next step! Patil, you are an expert in MCR. Thank you for helping me with all the mechanism issues and it is my pleasure to collaborate with you on the cyclization project. Wish you a successful future! I would also like to thank my Chinese friends in the Chemistry lab. Ruixue and Li, you will never truly know how happy I am to have had you two with me in the Chemistry lab. Lucky for me, I shared a room with you two in two different conferences, Ruixue

in Dusseldorf and Li in Athens. Ruixue, you are full of energy and we have a lot of similar topics and interests, such as playing LEGO and Animal Crossing. Please come back to Groningen soon, and I wish you success in finding a Postdoc position. Li, you are extremely hard-working and generous, and I always enjoyed the dinners held at your place. The girls’ talk with you inside and outside the lab always warmed my heart and gave me energy. I wish that you can finish all your projects successfully and publish some wonderful papers! Bidong, your expertise in medicinal chemistry is matched by your expertise in cooking. Your confidence and enthusiasm for drug discovery always inspired me. I wish you a glorious future and nice papers too! Qiang, Xin, and Xiaofang, it has been my pleasure to work with you all. Both of you are helpful, diligent, earnest, and positive. I believe that you all have brilliant careers ahead of you, and will have your names on a lot of excellent papers!

Special thanks to our biology lab colleagues! Wenjia, how lucky I am to have you as a friend! We have a lot of private talks and I could share all my happiness, my gossip and my complaints with you. It is also my great pleasure to have collaborated with you on the IL-17 project. I wish you all the best in Guangdong and that you find your true love soon. Chao,Ran, and Xiaochen thank you all for the nice moments, coffees in Eriba, and dinners together. I wish you all the best in what you do in future! Rick, thank you for scheduling the lab attendances and for all your additional help in the lab. Juliana, thank you for the warm talks every time we meet in the corridor and the elevator.

I am grateful to the former members of the lab, Yuanze, Dinos, Kai, Santosh, Chary,

Tryfon, Angelina, Angel, Maryam, Eman, Natalia, Vishwanatha, and Fernando. It is my great pleasure to work with you all. Also thanks to the visiting students who bring youth and vitality to our lab: Marta F, Federica, Francesca, Sara, Antonio, Miska,

Tatiana, Max, Kees, Harmen, Elmar, Perry, Gita, Jesse, Kumchok, John, Martin,

Danielle, Renan, Frans, Robert, Salomao, Oliver and many many more. Many thanks to my students, Vincenzo and Khaled. It was my pleasure to supervise you two for your Master’s projects. Both of you did excellent work in our lab, and produced publications to be proud of. I wish you the best of luck in your future and have every faith in you. Special thanks to Paola, Arianna, and Michel, your warm smiles and welcome events enriched my first year and eliminate the loneliness in Groningen. Many thanks!

Next, I would like to thank the friends who bring the most wonderful moments, fill the gaps, and paint the colors to my life in Groningen.

Acknowledgements

209

A

Xiaoxiang, you are the very first friend I made in the Netherlands and destined to be the most special one. In these four years, from small things in life to graduation and job hunting, we have shared information, encouraged each other, and felt sincere joy for each other's achievements. You are the very first person that I want to share any good or bad moments without hesitation. Nobody is perfect, but you are a perfect friend to me. Thank you for everything. Your knowledge of ancient poetry and prose is encyclopedic. It is always a pity for me that I have not been able to help you find your true love in these four years. Now I give all my luck to you, and wish you could meet the one who is true to you and can take care of you in next to no time.

Yu, you are the one from whom I learned the most. You are always optimistic and generous, you take care of everybody, and you could actively participate in all activities when we have a party together. Your attitude at work and the way you treat people is an inspiration. You seize what you have and push to earn the best future for yourself. Thank you for two pleasant and comfortable years living with you in your big house, and the four years enjoyable lunch time we have together in Eriba and de Brug. I will have these happy memories for the rest of my life. I am so excited to hear that you are going to have a baby in the coming year! I give all the best blessings to you and your cute child, and wish you could have wonderful achievements in your career.

Shuxian, you are one of the most precious friends that I have met in Groningen. You are straightforward, but treat people with sincerity. As well as your great academic achievements, I admire your attitude to daily life even more. Sometimes I feel like you are an emotional and life mentor to me. I could discover the fruit of wisdom from every word you say. For example, my 9th thesis proposition came from daily conversation with you. Futhermore, you are a good listener who can tolerent all my worries and complains, and gives helpful suggestions. I always looked forward to coming to your place and indulging with delicacies. I know you will earn many luminous accomplishments both in the academic field and in life.

Qian, my very first friend in the lab. We arrived on the same day and became officemates for the whole four years. You were always on standby whenever I needed your help or input. Thank you for your assistance inside and outside the lab. We are more than officemates and colleagues, as we are close friends. You are well versed in the art of speaking and I appreciate the happiness you bring to our work. I wish you fortune in finding your true love very soon, and all the best at Columbia University.

Jinrui, you are gentle, smart, and erudite. You and Shuxian are a match made in heaven, and I wish you two both a lifetime of happiness. Hao, thanks for taking care of Maodan

and for all the fancy trips that you planned. You are like a walking travel map! Daozheng, you are kind-hearted and have a beautiful voice. I hope all the best for you with your projects and nice papers. Weier, the "pistachio" of our Dolomites group, I enjoyed the trip with you, and thank you for the typical Peking recipe of zhajiangmian. Dear Lin, we have a lot to talk about because both of us raise pets. You are as beautiful and cute as your little cat, Mengmeng. You are hardworking and have a clear goal for your academic future. I wish you success with all your projects and I hope you could reunite with Bin in the early future.

Many thanks to other Chinese friends at the University of Groningen. Thank you

Fangyuan for our "Honor of Kings" happy hour; Siwei and Siqi for our delightful lunchtime in Eriba; Shanshan, Keni, Yizhou and Yana, for the unforgettable Iceland trip; Jingjing for the delicious food; and Zhangping, Guangcai, Liangliang, Haigen,

Xiaoxuan, Deng, Dan, Mei, Fan, Yanmei, Xiangyuan, Kun for the pleasurable talks and wonderful time.

I must also extend my warm thanks to dear old friends in China. Shuang and Biyu,

Yue and Chen, even though there is a huge distance between us, our friendships have become ever more sweet and solid. Thank you all for coming into my life and becoming friends with me. Thank you for listening to my little complaints, enlightening me, and always standing by my side no matter the situation. We are more like family members than friends. All the best wishes to you, and I hope to see you soon.

I sincerely thank the Chinese Scholarship Council for offering this great opportunity to conduct my Ph.D. study at the University of Groningen. Many thanks to my supervisors during my Master's study, Prof. Wenfang Xu and Prof. Yingjie Zhang, thank you for your guidance and supervision. I would also like to thank my former colleagues,

Xiaoyang, Yuqi, Xuewu, Xue, Jinning, Yongzheng, Jie, Shuai, Qinge, Qianwen. Wish to meet you in China soon.

My dear Bingquan, both of us are bashful to express our love, but I can strongly feel it, when you always be the first one to apologize while we had a quarrel (or let' say when I am angry, because you are never mad at me), and when you said you will give me a peaceful and prosperous future with your steady eyes. You said that you are thinking of our marriage since the beginning of our relationship, and I could tell you that you have

Acknowledgements

211

A

already become a permanent resident in my life. I have the courage to face everything as long as you are by my side. You are the most solid crutch of me and I could not finish my Ph.D. without your support. No word can express how important you are to me. Thank you, for everything.

I would also like to thank my cute "daughter" Maodan, having you as a family member is the best and happiest decision that I have ever made. Your smiling face and wagging tail could easily melt away my fatigue from work in an instant. Thank you for trusting me and being my pet, and I love everything about you, even your loud snore.

Finally, I want to thank my beloved family.

最后，我想诚挚的感谢我的家人。亲爱的爸爸妈妈，从小你们就用全部的心血培养 我，希望我能够成为一个幸福快乐，自力更生，最好能对社会有用的人。你们俩就 是我从小到大的榜样，谢谢你们教我真诚待人，常怀感恩的心。也谢谢你们无私的 爱和包容，让我能够不惧风雨，勇敢的在外闯荡。爸爸，倔强的你总在视频的时候 说，你妈妈想你了，其实我知道，是你也想我了，博士生涯结束，回到祖国之后，我 会给你们多些时间陪伴。妈妈，虽然你经常数落我又胖了，督促我少吃多动，我知 道你是希望我能健康生活，回国之后我们俩互相监督一起锻炼。世界上最可爱的奶 奶，感谢你给了我满满的爱，我从小在你的教导下长大，你的鼓励和陪伴是我努力 生活的动力。这四年多远离家乡，我的博士学习能够顺利结束，离不开你们在背后 的支持，爸爸妈妈奶奶，我希望你们都能健健康康平平安安，我还想和你们一起走 过接下来的几十个四年。

Jingyao Li

l

1. J Li, V Di Lorenzo, P Patil, A J Ruiz Moreno, K Kurpiewska, J Kalinowska-Tłuścik, M A Velasco-Velázquez, A Dömling*, Scaffolding-induced property modulation of chemical space, ACS Combinatorial Science, 2020, 22(7), 356-360.

2. M Konstantinidou, J Li, B Zhang, Z Wang, S Shaabani, F Ter Brake, K Essa, A Döm-ling*, PROTACs–a game-changing technology, Expert opinion on drug discovery, 2019, 14(12), 1255-1268.

3. Lunev, S., Bosch, S. S., Batista, F. A., Wang, C., Li, J., Linzke, M., ... & Groves, M. R. Identification of a non-competitive inhibitor of Plasmodium falciparum aspartate transcarbamoylase. Biochemical and biophysical research communications, 2018, 497(3), 835-842.

4. A L Chandgude1_{, J Li}1_{, A Dömling*, 2‐Nitrobenzyl Isocyanide as a Universal}

Convert-ible Isocyanide, Asian journal of organic chemistry. 2017, 6(7), 798-801(Co-first au-thor).

5. X Wang, X Li, J Li, J Hou, Y Qu, C Yu, F He, W Xu, J Wu*, Design, synthesis, and prelim-inary bioactivity evaluation of N1‐hydroxyterephthalamide derivatives with indole cap as novel histone deacetylase inhibitors, Chemical biology & drug design, 2017, 89(1), 38-46.

6. X Li, Y Zhang, Y Jiang, J Wu, E S Inks, C J Chou, S Gao, J Hou, Q Ding, J Li, X Wang, Selective HDAC inhibitors with potent oral activity against leukemia and colorectal cancer: design, structure-activity relationship and anti-tumor activity study. Euro-pean journal of medicinal chemistry, 2017,134, 185-206.5.

7. J Li, X Li, X Wang, J Hou, J Zang, S Gao, W Xu, Y Zhang*, PXD101 analogs with L‐phe-nylglycine‐containing branched cap as histone deacetylase inhibitors, Chemical bi-ology & drug design, 2016, 88(4), 574-584.

8. J Li, Y Zhang, W Xu*, Graphical synthetic routes of palbociclib, Chinese Journal of Medicinal Chemistry, 2016, 26(3), 263-265.

Manuscript in preparation

1. J Li1_{, A L Chandgude}1_{, A Dömling*, Tetrazole Building Blocks Strategy Towards}

Syn-thesis of Drug-like Molecules, (in submission)

2. J Li, A Dömling*, Phthalimide as the acid component in the passerini reaction: one-pot access to β-amidine alcohols, (in submission)

3. W Wang1_{, J Li}1_{, P Galatello, A R Romero, R Oerlemans, M Luberink, M R Groves* & A}

Domling*, Amino acid derivatives as a scaffold for the discovery of IL-17A binders. (in submission, Co-first author)

4. J Li, K Essa, E Surmiak, L Skalniak, T A Holak, A Dömling*, Design, synthesis and bio-activity evaluation of MCR based MDM2 PROTACs. (manuscript in preparation) 5. J Li, A Dömling*, Pd catalyzed isocyanide insertion to the formation of bi-functional

Conferences

213

A

C

12/2020 FIGON Dutch Medicine Days, Online, The Netherlands (Poster presentation, best poster award)

09/2019 5th EFMC International Symposium on advances in Synthetic and Medicinal Chemistry, Athens, Greece (Poster presentation)

08/2018 7th International Conference on Multicomponent Reactions and Related Chemistry, Düsseldorf, Germany (Poster presentation)

10/2018 FIGON Dutch Medicine Days, ReeHorst, Ede, The Netherlands (Poster presentation)

06/2017 Pharmacy Day 2017, Groningen, The Netherlands (oral presentation) 11/2013 4th National Conference on Medicinal Chemistry in China, Jinan, China

A

Jingyao Li was born on January 5th, 1993 in Taian, China. In June 2013, she obtained her Bachelor's degree major in Pharmacy from the CHina Pharmaceutical Univeristy in Nanjing, China. In June 2016, she earned her Master degree in Medicinal Chemistry from Shandong University under the supervision of Prof. Wenfang Xu and Prof. Yingjie Zhang. In the Master program, she was developed and synthesized a series of PXD101 analogs with L‐phenylglycine‐containing branched cap targeting histone deacetylase and investigated the in vitro bioactivity of them. In October 2016, she moved to the University of Groningen and decided to continue her study in organic chemistry and drug discovery at the department of Drug Design under the supervision of Prof. dr. Alexander Dömling. Her research interests are enlarge the scaffold diversities by exploring substrates and post-cyclization of multicomponent reactions as well as the applications in medicinal chemistry targeting IL-17A and the development of MDM2 PROTACs.