University of Groningen

Multicomponent reactions, applications in medicinal chemistry & new modalities in drugdiscoveryKonstantinidou, Markella

DOI:10.33612/diss.111908148

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Citation for published version (APA):Konstantinidou, M. (2020). Multicomponent reactions, applications in medicinal chemistry & new modalitiesin drug discovery. [Groningen]: Rijksuniversiteit Groningen. https://doi.org/10.33612/diss.111908148

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APPENDIX

ABOUT THE AUTHOR

PUBLICATIONS

CONFERENCES

ACKNOWLEDGEMENTS

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ABOUT THE AUTHOR

Markella was born on the 21st of April 1989 in Thessaloniki, Greece. In July 2012 she graduated with

a Degree in Pharmacy from the Aristotle University of Thessaloniki, Greece. In the same University

she pursued post-graduate studies and in 2014 she obtained her MSc in Medicinal Chemistry. Her

MSc thesis entitled “Design and synthesis of biologically active compounds bearing the cinnamic

/ propenonic scaffold” was performed under the supervision of Prof. Dimitra Hadjipavlou – Litina.

Shortly after completing her master studies, she was employed as a research assistant at the Institute

of Biology, Medicinal Chemistry and Biotechnology in the National Hellenic Research Foundation

in Athens. She performed multi-step synthesis of dendrimers with biological applications under

the supervision of Dr. Barry Steele and Dr. George Heropoulos. In February 2016, she moved to

Groningen to pursue doctoral studies under the supervision of Prof. Alexander Dömling, in the

group of Drug Design at the Department of Pharmacy. Her research focused on novel synthetic

methodologies based on multicomponent reactions, applications in medicinal chemistry and

new modalities, such as proteolysis targeting chimeras in drug discovery. During her PhD, she did

a 3-month secondment in AstraZeneca, in Gotherburg, Sweden, focusing on virtual screening and

docking, under the supervision of Dr. Hongming Chen. Her PhD position was part of a Marie Curie

ITN network with the acronym AEGIS (accelerated early stage drug discovery).

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PUBLICATIONS

1 M. Konstantinidou, J. Li, B. Zhang, Z. Wang, S. Shaabani, F. ter Brake, K. Essa, A.Dömling, PROTACs – a game changing technology, Expert Opinion on Drug Discovery 2019, 14, 1255 – 1268, DOI: 10.1080/17460441.2019.1659242

2. Q. Wang, K.C. Mgimpatsang, M. Konstantinidou, S. V. Shishkina, A. Dömling, 1,3,4-Oxadiazoles by Ugi-tetrazole and Huisgen reactions, Organic Letters 2019,21, 7320 – 7323, DOI: 10.1021/acs.orglett.9b02614

3. Q. Wang, A. Osipyan, M. Konstantinidou, R. Butera, K. C. Mgimpatsang, S. V. Shishkina, A. Dömling, Pd-Catalyzed de novo assembly of diversely substituted indole-fused polyheterocycles, Journal of Organic Chemistry 2019, 84, 12148 – 12156, DOI: 10.1021/acs.joc.9b01258

4. S. Kurhade,†M. Konstantinidou,†F.Sutanto, K. Kurpiewska, J. Kalinowska –Tłuscik, A. Dömling, SEQUENTIAL MULTICOMPONENT SYNTHESIS OF 2-(IMIDAZO[1,5-α]PYRIDIN-1-YL)-1,3,4-OXADIAZOLES, European Journal of Organic Chemistry 2019, 10, 2029-2034, DOI: 10.1002/ejoc.201801880

5. R.Madhavachary,† N.Naveen,† Y. Wang, Q. Wang, M. Konstantinidou, A. Dömling, beta-Carbolinone analogues from the Ugi silver mine, European Journal of Organic Chemistry 2018, 24, 3139-3143, DOI: 10.1002/ejoc.201800557

6. M. Konstantinidou, K. Kurpiewska, J. Kalinowska-Tłuscik, A. Dömling, Glutarimide alkaloids through multicomponent reaction chemistry, European Journal of Organic Chemistry 2018, 47, 6714-6719, DOI: 10.1002/ejoc.201801276

7. M.Konstantinidou, T. Zarganes – Tzitzikas, K. Magiera, T.A. Holak, A. Dömling, Immune Checkpoint PD-1/PD-L1: Is there life beyond antibodies? Angewandte Chemie International Edition 2018, 57, 4840-4848, DOI: 10.1002/anie.201710407

8. T. Zarganes-Tzitzikas, M. Konstantinidou, Y. Gao, D. Krzemien, K. Zak, G. Dubin, T.A. Holak, A. Dömling. Inhibitors of programmed cell death 1 (PD-1): a patent review (2010-2015), Expert Opinion on Therapeutic Patents 2016, 26, 973-977, DOI:10.1080/13543776.2016.1206527

9. M. Konstantinidou, A. Gkermani, D. Hadjipavlou-Litina, Synthesis and pharmacochemistry of new pleiotropic pyrrolyl derivatives, Molecules 2015, 20, 16354-16374, DOI:10.3390/molecules200916354

10. A. Vronteli, D. Hadjipavlou-Litina, M. Konstantinidou, K.E. Litinas, Synthesis of fused Pyranocarbazolones with biological interest, Arkivoc 2015 (iii) 111-123, DOI: 10.3998/ark.5550190.p009.004

11. M. Konstantinidou, D. Hadjipavlou-Litina, Cytokines in terms of QSAR. Review, evaluation, comparative studies, SAR QSAR Environ. Res. 2013, 24, 883-962, DOI: 10.1080/1062936X.2013.815656.

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CONFERENCES

Oral presentations 1. Discovery of proteolysis targeting chimeras for leucine-rich repeat kinase 2 (LRRK2), New

Frontiers in structure-based drug discovery, 23-25/9/2019, Florence, Italy2. Tetrazole and oxadiazole heterocycles via multicomponent reaction schemes, ACS Fall

National Meeting, 25-29/8/2019, San Diego, USA3. Design of a multicomponent reaction scaffold with inhibitory activity on aspartic proteases,

ACS Fall National Meeting, 25-29/8/2019, San Diego, USA4. Applications of multicomponent reaction chemistry in heterocyclic synthesis, ACS Spring

National Meeting, 31/3-1/4/2019, Orlando, USA5. Design of a MCR scaffold with inhibitory activity on aspartic proteases, 7th International

Conference on Multicomponent Reactions and Related Chemistry, 26-31/8/2018, Düsseldorf, Germany

6. Discovery of unprecedented aspartic-protease inhibitors with applications in Alzheimer and other diseases, 25th Young Research Meeting, SCT, 5-7/3/2018, Orleans, France

Poster presentations1. Recent advances in heterocyclic synthesis via multicomponent reaction schemes, EFMC

International Symposium on Advances in Synthetic and Medicinal Chemistry (EFMC-ASMC), 1-5/9/2019, Athens, Greece

2. Inhibitors for Asp-proteases: anchor-based virtual screening, innovative chemistry and protein crystallography, ACS Spring National Meeting, 31/3-1/4/2019, Orlando, USA

3. Discovery of unprecedented aspartic-protease inhibitors with applications in Alzheimer and other diseases,FIGON Dutch Medicine Days 1-2/10/2018

4. Design and synthesis of small molecules as protein-protein interaction stabilizers,5th EFMC Young Medicinal Chemist Symposium (EFMC-YMCS) 6-7/9/2018, Ljubljana, Slovenia

5. From fragment hits to MCR small molecules: design, synthesis and biological evaluation,, XXV EFMC International Symposium on Medicinal Chemistry (EFMC-ISMC) 2-6/9/2018, Ljubljana, Slovenia

6. Glutarimide alkaloids via MCR chemistry, 53rd International Conference on Medicinal Chemistry, 5-7/7/2017, Toulouse, France

7. New glycodendrimers as potential carriers for anticancer drugs, Frontiers in Medicinal Chemistry, 14-16/9/2015, Antwerp, Belgium

8. Synthesis of new poly-hydroxy-dendrimers as iron chelators, 12th Chemistry Conference Greece-Cyprus, 8-10/5/2015, Thessaloniki, Greece

9. Design and synthesis of acrylic acid derivatives, 21st Young Research Fellow Meeting, 24-25/03/2014, Montpellier, France

10. Synthesis and biological evaluation of structurally modified acrylic acid derivatives, 16th Hellenic Pharmaceutical Congress, 31/05-03/06/2013, Athens, Greece

11. QSAR of CXCR2 chemokine receptor antagonists as potent anti-inflammatory agents, 19thEuroQSAR, 26-30/08/2012, Vienna, Austria

12. QSAR of interleukin inhibitors and antagonists: a tool for anti-inflammatory drug design, 15th Hellenic Symposium on Medicinal Chemistry, 25-27/05/2012, Athens, Greece

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ACKNOWLEDGEMENTS

This is the end of the four years of my PhD journey in the Netherlands. In retrospect, it was an

amazing experience not only scientifically, but also personally. Here I would like to express my

gratitude to the people who shared this journey with me and made it truly memorable.

First and foremost, I am truly grateful to my supervisor Prof. Alex Dömling for giving me the

opportunity to join the Drug Design group as a PhD fellow within the ITN AEGIS. Your support,

guidance and persistent enthusiasm about new ideas and projects are really remarkable. You

greeted me every morning with a “kalimera” and invited me to lovely dinners with excellent wine.

I was involved in numerous projects in the lab and you always gave me freedom and listened to

my ideas, allowing me to work independently. I would really like to thank you for giving me the

chance to attend and present my work in international conferences and in particular the two ACS

meetings in my last year. Many thanks for giving me the chance to learn your unique chemistry of

multicomponent reactions (MCRs) and for getting me involved in the new modality of PROTACs.

Thank you for everything!!!

I would also like to thank my co-promotor Prof. Tad Holak for the smooth and fruitful collaborations.

It was a pleasure to meet you in the conference in Toulouse.

Moreover, I would like to acknowledge Dr. Hongming Chen and Dr. Ola Engkvist for the

enjoyable stay in AstraZeneca, Gothenburg. During those three months I learned a lot regarding

computational chemistry and had the chance to experience the industrial aspect of drug discovery.

I would also like to thank the members of the reading committee: Prof. Frank Dekker, Prof. Philip

Elsinga and Prof. Romano Orru for their time and effort to evaluate and approve the thesis.

Next, I would like to acknowledge Dr. Matthew Groves for introducing me to structural biology

during my short stay in his lab.

Many thanks to Prof. Carlos Camacho for helping me with the AnchorQuery software, the

interesting conversations and for being good company in the AEGIS schools.

My AEGIS fellows and friends, Ave, Joy, Ryan, Roberto, Maxime, Atilio, Charlie, Engi, Francesca,

Valeria, Patrick, João, Giulia, Laura, you made this experience truly unique since the first time we

met in Munich. I have great memories from the winter and summer schools in Uppsala, Munich,

Groningen, Basel, Paris and Florence. I wish you all the best in your future steps. I am also grateful

to Dr. Eva Schlosser for the coordination, help and support within the AEGIS consortium. Many

thanks for offering me the opportunity to give an oral presentation in the final conference in

Florence. This resulted in meeting interesting people and also getting my next job.

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Jolanda, you always greeted me with a smile and you were extremely helpful with various

administrative issues, conferences and sending packages. Thanks a lot!

I am grateful to our lab manager Dr. André Boltjes for his invaluable contribution in maintaining

the lab in a non-chaotic state. You were always eager to discuss chemistry problems and gave

me valuable advice. I enjoyed working with you on the adenine mimetics project. Thank you very

much for helping me with the procedures for the thesis. I wish you all the best!

Robin, our second lab manager, thank you for translating the summary of my thesis in Dutch. You

were always eager to assist in equipment problems. You have a great sense of humour and of course

the superpower of scheduling me for presentations in the lab meetings on the days that I was not

there. Probably at a certain point I will start missing your unconventional music choices in the lab.

I would like to express my gratitude to my dear friends and paranymphs Qian and Jingyao. Qian,

you are truly a “cosmopolitan” Chinese. You were always greeting me with a big smile. I really

enjoyed collaborating with you. You are very hard-working and your contribution in various

projects was truly valuable. I will miss you enthusiasm and your singing in the lab. Jingyao, my

former office mate, it was always a pleasure discussing with you. Both of you were the first Chinese

I met in the lab and introduced me to Chinese food, music and cultural aspects that I was unaware

of. I hope we can meet once in your beautiful county.

Roberto, one of my current office mates, I really enjoyed all the conversations regarding

troubleshooting chemistry problems and discussing interesting old-school chemistry reactions

(which seem to be your favourite) and the more recent palladium-catalyzed reactions that we

performed together successfully. You somehow combine the Sicilian spirit (and cooking skills)

with the German discipline and hard work.

Fandi, Ruixue, Zefeng, Bidong, Li it was a pleasure working with you all. Thank you for the

interesting Indonesian and Chinese dinners. It made me really happy attending the conference in

Athens with you and introducing you to Greek food (and Greek islands).

I would also like to thank all the current lab members Xin, Qiang, Maryam, Angelina, Marta W,

Angel, Mosjan, Patil, Shabnam for the nice atmosphere in the lab and also the members of the

structural biology lab Kai, Fernando, Wenja, Sergey, Juliana for welcoming me there and teaching

me the secrets of the “dark side”.

I am grateful to former members of the lab Natalia, Edwin, Eman, Vishnu, Yuanze, Naveen, Ajay.

It was a pleasure meeting you all. Santosh, my friend, a learned a lot from you. We had plenty of

interesting discussions and collaborated very well together. I really enjoyed the stories you shared

during lunch time about India.

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Over the years we had so many visiting students from all over the world. I would like to thank in

particular Arianna, with whom I have great memories from my first year in the lab, including Dutch

courses, dinners and numerous trips within the Netherlands. It was a pleasant surprise to see you

again recently in the conference in Athens.

I would also like to thank my former students Zlata and Dario. You were both hard-working,

diligent and I really enjoyed working with you. Hope to see you again.

Many thanks to visiting students that made the lab truly international: Marta F, Federica, Francesca,

Sara, Antonio, Miska, Tatiana, Max, Kees, Harmen, Elmar, Michel, Perry, Gita, Vincenzo, Kumchok,

Martin, Danielle, Paola, Renan, Frans, Khaled, Robert, Salomão, Oliver (thanks for the great drawings

on the fumehoods) and many many more.

This whole experience would have been completely different and probably less fun without our

small Greek community. Dinos, Tryfonas, Nikos, Giorgos, Evi, Valanto, Georgia, Despoina, Tassis

thank you having me in your company and enjoying together Saturday coffees, drinks, dinners,

PhD defences and much more. Dinos and Tryfonas, the original Greeks of the Drug Design Group,

I cannot thank you enough for your help, solidarity and friendship not only in the lab, but also in

our everyday life. Your chemistry expertise and guidance helped me a lot to adjust. Nikos, Giorgos

and Valanto, I really enjoyed spending time with you.

I would also like to thank my former supervisor during my master, Dr. Dimitra Hadjipavlou-Litina,

who was the first to introduce me in the area of medicinal chemistry and has always encouraged

me. My dear friends from this lab, Katerina, Eleni, Maria, Xristos, Thaleia, Anna-Maria, who are

always eager to meet and spend time together. Moreover, my supervisors in the National Hellenic

Research Foundation, Dr. George Heropoulos and Dr. Barry Steele for the valuable experience

there. Cecile, Georgia and Yakinthi thanks for the great memories.

Finally, I would like to thank my beloved family for the love, encouragement and support during

this long journey.

Markella

18/11/2019

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