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Mark Cushman

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Mark S. Cushman is an American chemist, whose primary research is in the area of medicinal chemistry. He completed his pre-pharmacy studies at Fresno State College (now California State University, Fresno) in 1965. He then attended the University of California San Francisco (as a University of California Regents Scholar), earning a Pharm.D. in 1969 and a Ph.D. in Medicinal Chemistry in 1973. Thereafter, he performed postdoctoral training in the laboratory of George Büchi, Ph.D., at the Massachusetts Institute of Technology (MIT). There, his research focused on the discovery and development of new synthetic methodologies,[1] and the isolation and structural characterization of mycotoxins from Aspergillus niger.[2] In 1975, he joined the Department of Medicinal Chemistry and Molecular Pharmacology (at the time, Department of Medicinal Chemistry and Pharmacognosy) at Purdue University. From 1983 to 1984, Prof. Cushman was a Senior Fulbright Scholar at Munich Technical University working in the laboratory of Professor Adelbert Bacher. His sabbatical work dealt with the design and synthesis of probes to elucidate key aspects of the biosynthesis of riboflavin (vitamin B2).[3] Currently he holds the rank of Distinguished Professor Emeritus of Medicinal Chemistry at Purdue University.[4] He has mentored 40 graduate students, 59 postdoctoral researchers, and 5 visiting scholars. He has published 348 papers and holds 41 patents. His work has ~17,000 citations with an h-index of 69. His most cited papers had 471, 403, and 299 citations as of August 2021.[4] He has made seminal contributions to the fields of synthetic and medicinal chemistry including the development of new synthetic methodologies, the synthesis of natural products, and the preparation of antivirals, antibacterials, and anticancer agents, and mechanism probes to understand the function of over thirty macromolecular targets.[4] One of his main scientific contributions is the development of the indenoisoquinolines, molecules that inhibit the action of toposiomerase I (Top1) and stabilize the G-quadruplex in the Myc promoter.[5] Three indenoisoquinolines designed and synthesized by his research group at Purdue University [indotecan (LMP 400), indimitecan (LMP 776), and LMP 744] demonstrated potent anticancer activity in vivo and have completed phase I clinical trials at the National Institutes of Health.[6]

Personal life

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Mark Cushman was born on August 20, 1945, in the city of Fresno, California.  A main influence during his formative years was his maternal grandfather, Stanley Borleske, who taught engineering and mathematics at Fresno State College. Mr. Borleske also worked as head football, basketball, and baseball coach at Fresno State College. Besides instilling his love for football, his grandfather influenced traits such as coaching/mentoring, hard-work, a special attention to detail, planning, ethics, and love for learning. These attributes have been the hallmarks of Professor Cushman's character.[7] 

The Castagnoli-Cushman reaction

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Synthesis of an indenoisoquinoline using the Castagnoli-Cushman reaction

In the 1970's, while working in the group of Neal Castagnoli, Jr., Ph.D., he reported and studied in detail the condensation of cyclic anhydrides with imines[8] (work that was based on a previous report by Castagnoli[9]). This reaction is currently known as the Castagnoli-Cushman reaction. One of its first applications was for the preparation of nitrogen analogues of tetrahydrocannabinol, a pharmacologically active natural product isolated from Cannabis sativa.[10] This versatile transformation has been used to generate polysubstituted lactam carboxylic acids and to prepare benzophenanthridine and protoberberine alkaloids, and hundreds of indenoisoquinolines.[11][12][13] A general scheme of the Cushman-Castagnoli reaction, applied to the synthesis of a model indenoisoquinoline, is shown to the right. Later, the conditions were optimized and include the formation of an acyl chloride followed by condensation using AlCl3.[14][15]

Development of the indenoisoquinolines

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An alternative synthetic method for the preparation of an indenoisoquinoline

Dr. Cushman is the world leader in the design and synthesis of the indenoisoquinolines.[16] These drugs, which were discovered serendipitously during a synthesis of the antileukemic agent nitidine chloride, can eradicate cancer cells. The seminal paper describing the synthesis of the molecules, using the Castagnoli-Cushman Reaction, was published in The Journal of Organic Chemistry.[17]  Alternatively, the indenoisoquinolines can be prepared by reacting a benz[d]indeno[1,2-b]pyran-5,11-dione (I) with an amine (II).

Initially, it was discovered the indenoisoquinolines inhibited the action of the topoisomerase I enzyme.[18][19] Later, it was found these molecules can also affect other targets including the retinoid X receptor (RXR),[20] poly [ADP-ribose] polymerase 1 (PARP-1),[21] topoisomerase II,[22] estrogen receptor,[23] vascular endothelial growth factor-2 (VEGFR-2),[23] hypoxia-inducible factor 1-alpha (HIF-1a),[24] tyrosyl DNA phosphodiesterases (TDP) 1 and 2, and G-quadruplexes.[5]

In addition, the Cushman group and collaborators have reported that indenoisoquinolines could potentially treat other diseases including visceral Leishmaniasis, African trypanosomiasis (sleeping sickness), and Angelman syndrome.

Total synthesis

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Selected natural products synthesized by Mark Cushman and co-workers

Another main contribution of Mark Cushman and his group deals with the synthesis of various natural products and pharmacologically active synthetic substances. Some of the compounds his group prepared include: the antileukemic agent nitidine chloride (III);[25] corydaline,[26] which possesses antinociceptive and antiallergic activities among others; thalictricavine,[27] an inhibitor of human acetylcholinesterase and butyrylcholinesteras;[28] berlambine;[27] (±)-canadine; (+)-thalictrifoline;[29] cosalane (IV),[30] a molecule that inhibits HIV by acting on various targets;[31] (±) chelidonine,[32] a non-specific cholinesterase inhibitor; ammosamide B (V),[33] a cytotoxic natural product that targets myosin;[34] lavendustin A (VI),[35] a tyrosine kinase inhibitor;[36] and (+)- and (–)-corynoline.[37][38]

Awards and honors

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Professor Cushman has received various awards including:

  • Purdue University Chapter of Sigma Xi Research Award in Science and Engineering (2019)[39]
  • The Philip S. Portoghese Joint Lectureship sponsored by the Journal of Medicinal Chemistry and the ACS Division of Medicinal Chemistry (2018)[40]
  • The Ole Gisvold Lectureship in Medicinal Chemistry from the Department of Medicinal Chemistry at the University of Minnesota (2018)[41]
  • Fellow of the National Academy of Inventors (2018)[42]
  • Highly Prolific Author by the Journal of Medicinal Chemistry (2017)[43]
  • Purdue Innovators Hall of Fame Inductee (2016)[44]
  • The University of California San Francisco 150th Anniversary Alumni Excellence Award (2015)[45]
  • The Webster-Sibilsky Lecturer, University of Illinois (2012)[46]
  • Fellow of the American Association for the Advancement of Science (2012)[47]
  • Chaney Scholar Award for Exceptional Research (2012)[48]
  • Purdue Cancer Research Award (2004)[49]
  • National Institutes of Health Postdoctoral Fellowship (1973–1975)[50]
  • Senior Fulbright Scholar (1983–1984)[50]

Others

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Dr. Cushman served on the Editorial Advisory Board of The Journal of Organic Chemistry (1999–2004). He also served on the Editorial Advisory Board (2005–2010) and as Associate Editor (2012–2020) of The Journal of Medicinal Chemistry. He is a member of the Board of Directors of Gibson Oncology.

References

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  1. ^ Buchi, George; Cushman, Mark; Wuest, Hans (1974-08-01). "Conversion of allylic alcohols to homologous amides by N,N-dimethylformamide acetals". Journal of the American Chemical Society. 96 (17): 5563–5565. doi:10.1021/ja00824a041. ISSN 0002-7863.
  2. ^ Anderegg, Robert J.; Biemann, Klaus; Buechi, George; Cushman, Mark (1976-05-01). "Malformin C, a new metabolite of Aspergillus niger". Journal of the American Chemical Society. 98 (11): 3365–3370. doi:10.1021/ja00427a051. ISSN 0002-7863. PMID 1262650.
  3. ^ Cushman, Mark; Patrick, Donald A.; Bacher, Adelbert; Scheuring, Johannes (1991-07-01). "Synthesis of epimeric 6,7-bis(trifluoromethyl)-8-ribityllumazine hydrates. Stereoselective interaction with the light riboflavin synthase of Bacillus subtilis". The Journal of Organic Chemistry. 56 (15): 4603–4608. doi:10.1021/jo00015a009. ISSN 0022-3263.
  4. ^ a b c "Mark S. Cushman". Retrieved August 24, 2021.
  5. ^ a b Wang, Kai-Bo; Elsayed, Mohamed S. A.; Wu, Guanhui; Deng, Nanjie; Cushman, Mark; Yang, Danzhou (2019-07-17). "Indenoisoquinoline Topoisomerase Inhibitors Strongly Bind and Stabilize the MYC Promoter G-Quadruplex and Downregulate MYC". Journal of the American Chemical Society. 141 (28): 11059–11070. doi:10.1021/jacs.9b02679. ISSN 0002-7863. PMC 7307421. PMID 31283877.
  6. ^ Pommier, Yves; Cushman, Mark; Doroshow, James H. (2018-12-18). "Novel clinical indenoisoquinoline topoisomerase I inhibitors: a twist around the camptothecins". Oncotarget. 9 (99): 37286–37288. doi:10.18632/oncotarget.26466. ISSN 1949-2553. PMC 6324668. PMID 30647868.
  7. ^ Conda-Sheridan, Martin (2019). "Editorial page, special issue honoring Professor Mark Cushman". Medicinal Research Reviews. 39 (4): 1233–1234. doi:10.1002/med.21583. ISSN 1098-1128. PMID 31194276.
  8. ^ Castagnoli, Neal; Cushman, Mark (November 1971). "Condensation of succinic anhydrides with Schiff bases. Scope and mechanism". The Journal of Organic Chemistry. 36 (22): 3404–3406. doi:10.1021/jo00821a029. ISSN 0022-3263. PMID 5132298.
  9. ^ Castagnoli, Neal (1969-10-01). "Condensation of succinic anhydride with N-benzylidene-N-methylamine. Stereoselective synthesis of trans- and cis-1-methyl-4-carboxy-5-phenyl-2-pyrrolidinone". The Journal of Organic Chemistry. 34 (10): 3187–3189. doi:10.1021/jo01262a081. ISSN 0022-3263. PMID 5811404.
  10. ^ Cushman, M.; Castagnoli, N. (1974-05-31). "Synthesis of pharmacologically active nitrogen analogs of the tetrahydrocannabinols". The Journal of Organic Chemistry. 39 (11): 1546–1550. doi:10.1021/jo00924a021. ISSN 0022-3263. PMID 4833507.
  11. ^ Mikheyev, Alexander; Kantin, Grigory; Krasavin, Mikhail (May 2018). "Aldazines in the Castagnoli–Cushman Reaction". Synthesis. 50 (10): 2076–2086. doi:10.1055/s-0037-1609375. ISSN 0039-7881. S2CID 103885937.
  12. ^ Howard, Sara Y.; Di Maso, Michael J.; Shimabukuro, Kristin; Burlow, Noah P.; Tan, Darlene Q.; Fettinger, James C.; Malig, Thomas C.; Hein, Jason E.; Shaw, Jared T. (2021-08-05). "Mechanistic Investigation of Castagnoli–Cushman Multicomponent Reactions Leading to a Three-Component Synthesis of Dihydroisoquinolones". The Journal of Organic Chemistry. 86 (17): 11599–11607. doi:10.1021/acs.joc.1c01163. ISSN 0022-3263. PMID 34351161. S2CID 236927425.
  13. ^ Firsov, Andrei; Chupakhin, Evgeny; Dar’in, Dmitry; Bakulina, Olga; Krasavin, Mikhail (2019-03-15). "Three-Component Castagnoli–Cushman Reaction of 3-Arylglutaconic Acids with Aromatic Aldehydes and Amines Delivers Rare 4,6-Diaryl-1,6-dihydropyridin-2(3H)-ones". Organic Letters. 21 (6): 1637–1640. doi:10.1021/acs.orglett.9b00171. ISSN 1523-7060. PMID 30794425. S2CID 73506357.
  14. ^ Morrell, Andrew; Antony, Smitha; Kohlhagen, Glenda; Pommier, Yves; Cushman, Mark (2004-07-16). "Synthesis of nitrated indenoisoquinolines as topoisomerase I inhibitors". Bioorganic & Medicinal Chemistry Letters. 14 (14): 3659–3663. doi:10.1016/j.bmcl.2004.05.022. ISSN 0960-894X. PMID 15203138.
  15. ^ Conda-Sheridan, Martin; Reddy, P. V. Narasimha; Morrell, Andrew; Cobb, Brooklyn T.; Marchand, Christophe; Agama, Keli; Chergui, Adel; Renaud, Amélie; Stephen, Andrew G.; Bindu, Lakshman K.; Pommier, Yves (2012-12-21). "Synthesis and Biological Evaluation of Indenoisoquinolines That Inhibit Both Tyrosyl-DNA Phosphodiesterase I (Tdp1) and Topoisomerase I (Top1)". Journal of Medicinal Chemistry. 56 (1): 182–200. doi:10.1021/jm3014458. ISSN 0022-2623. PMC 3542538. PMID 23259865.
  16. ^ Cushman, Mark (2021-12-08). "Design and Synthesis of Indenoisoquinolines Targeting Topoisomerase I and Other Biological Macromolecules for Cancer Chemotherapy". Journal of Medicinal Chemistry. 64 (24): 17572–17600. doi:10.1021/acs.jmedchem.1c01491. ISSN 0022-2623. PMID 34879200. S2CID 245065452.
  17. ^ Cushman, Mark; Cheng, Leung (1978-09-01). "Stereoselective oxidation by thionyl chloride leading to the indeno[1,2-c]isoquinoline system". The Journal of Organic Chemistry. 43 (19): 3781–3783. doi:10.1021/jo00413a036. ISSN 0022-3263.
  18. ^ Kohlhagen, Glenda; Paull, Kenneth D.; Cushman, Mark; Nagafuji, Pamela; Pommier, Yves (1998-07-01). "Protein-Linked DNA Strand Breaks Induced by NSC 314622, a Novel Noncamptothecin Topoisomerase I Poison". Molecular Pharmacology. 54 (1): 50–58. doi:10.1124/mol.54.1.50. ISSN 0026-895X. PMID 9658189.
  19. ^ Antony, Smitha; Jayaraman, Muthusamy; Laco, Gary; Kohlhagen, Glenda; Kohn, Kurt W.; Cushman, Mark; Pommier, Yves (2003-11-01). "Differential Induction of Topoisomerase I-DNA Cleavage Complexes by the Indenoisoquinoline MJ-III-65 (NSC 706744) and Camptothecin: Base Sequence Analysis and Activity against Camptothecin- Resistant Topoisomerases I". Cancer Research. 63 (21): 7428–7435. ISSN 0008-5472. PMID 14612542.
  20. ^ Park, Eun-Jung; Kondratyuk, Tamara P.; Morrell, Andrew; Kiselev, Evgeny; Conda-Sheridan, Martin; Cushman, Mark; Ahn, Soyoun; Choi, Yongsoo; White, Jerry J.; van Breemen, Richard B.; Pezzuto, John M. (April 2011). "Induction of retinoid X receptor activity and consequent up-regulation of p21WAF1/CIP1 by indenoisoquinolines in MCF7 cells". Cancer Prevention Research (Philadelphia, Pa.). 4 (4): 592–607. doi:10.1158/1940-6207.CAPR-10-0004. ISSN 1940-6207. PMC 5554444. PMID 21464033.
  21. ^ Jagtap, Prakash G.; Baloglu, Erkan; Southan, Garry J.; Mabley, Jon G.; Li, Hongshan; Zhou, Jing; van Duzer, John; Salzman, Andrew L.; Szabó, Csaba (2005-08-01). "Discovery of Potent Poly(ADP-ribose) Polymerase-1 Inhibitors from the Modification of Indeno[1,2-c]isoquinolinone". Journal of Medicinal Chemistry. 48 (16): 5100–5103. doi:10.1021/jm0502891. ISSN 0022-2623. PMID 16078828.
  22. ^ Marzi, Laetitia; Sun, Yilun; Huang, Shar-yin N.; James, Amy; Difilippantonio, Simone; Pommier, Yves (2020-08-01). "The Indenoisoquinoline LMP517: A Novel Antitumor Agent Targeting both TOP1 and TOP2". Molecular Cancer Therapeutics. 19 (8): 1589–1597. doi:10.1158/1535-7163.MCT-19-1064. ISSN 1535-7163. PMC 7415565. PMID 32430490.
  23. ^ a b Tang, Zhichao; Wu, Chengzhe; Wang, Tianlin; Lao, Kejing; Wang, Yejun; Liu, Linyi; Muyaba, Moses; Xu, Pei; He, Conghui; Luo, Guoshun; Qian, Zhouyang (2016-08-08). "Design, synthesis and evaluation of 6-aryl-indenoisoquinolone derivatives dual targeting ERα and VEGFR-2 as anti-breast cancer agents". European Journal of Medicinal Chemistry. 118: 328–339. doi:10.1016/j.ejmech.2016.04.029. ISSN 0223-5234. PMID 27176944.
  24. ^ Xu, Xiaoli; Liu, Fang; Zhang, Shengmiao; Jia, Jianmin; Li, Zhiyu; Guo, Xiaoke; Yang, Yong; Sun, Haopeng; You, Qidong (2013-10-01). "Indenoisoquinoline derivatives as topoisomerase I inhibitors that suppress angiogenesis by affecting the HIF signaling pathway". Biomedicine & Pharmacotherapy. 67 (8): 715–722. doi:10.1016/j.biopha.2013.06.004. ISSN 0753-3322. PMID 23932721.
  25. ^ Cushman, Mark; Cheng, Leung (January 1978). "Total synthesis of nitidine chloride". The Journal of Organic Chemistry. 43 (2): 286–288. doi:10.1021/jo00396a024. ISSN 0022-3263.
  26. ^ Cushman, Mark; Dekow, Frederick W. (1978-01-01). "A total synthesis of corydaline". Tetrahedron. 34 (10): 1435–1439. doi:10.1016/0040-4020(78)80162-8. ISSN 0040-4020.
  27. ^ a b Cushman, Mark; Dekow, Frederick W. (1979-02-01). "Synthesis of (.+-.)-thalictricavine, berlambine, and (.+-.)-canadine from a common intermediate". The Journal of Organic Chemistry. 44 (3): 407–409. doi:10.1021/jo01317a020. ISSN 0022-3263.
  28. ^ Chlebek, Jakub; Korábečný, Jan; Doležal, Rafael; Štěpánková, Šárka; Pérez, Daniel I.; Hošťálková, Anna; Opletal, Lubomír; Cahlíková, Lucie; Macáková, Kateřina; Kučera, Tomáš; Hrabinová, Martina (January 2019). "In Vitro and In Silico Acetylcholinesterase Inhibitory Activity of Thalictricavine and Canadine and Their Predicted Penetration across the Blood-Brain Barrier". Molecules. 24 (7): 1340. doi:10.3390/molecules24071340. PMC 6480038. PMID 30959739.
  29. ^ Iwasa, Kinuko; Gupta, Yash Pal; Cushman, Mark (1981-01-01). "The absolute configurations of (+)-thalictrifoline and (+)-corydalic acid methyl ester. Total synthesis of (+)-thalictrifoline". Tetrahedron Letters. 22 (25): 2333–2336. doi:10.1016/S0040-4039(01)82899-9. ISSN 0040-4039.
  30. ^ Cushman, Mark; Golebiewski, W. Marek; McMahon, James B.; Buckheit, Robert W.; Clanton, David J.; Weislow, Owen; Haugwitz, Rudiger D.; Bader, John P.; Graham, Lisa; Rice, William G. (September 1994). "Design, Synthesis, and Biological Evaluation of Cosalane, a Novel Anti-HIV Agent Which Inhibits Multiple Features of Virus Reproduction". Journal of Medicinal Chemistry. 37 (19): 3040–3050. doi:10.1021/jm00045a008. ISSN 0022-2623. PMID 7932526.
  31. ^ Zhan, Peng; Li, Zhenyu; Liu, Xinyong (September 2010). "Cosalane and its analogues: a unique class of anti-HIV agents". Mini Reviews in Medicinal Chemistry. 10 (10): 966–976. doi:10.2174/138955710792007222. ISSN 1875-5607. PMID 20540707.
  32. ^ Cushman, Mark; Choong, Tung-Chung; Valko, Joseph T.; Koleck, Mary P. (1980-12-01). "Total synthesis of (.+-.)-chelidonine". The Journal of Organic Chemistry. 45 (25): 5067–5073. doi:10.1021/jo01313a011. ISSN 0022-3263.
  33. ^ Reddy, P. V. Narasimha; Banerjee, Biplab; Cushman, Mark (2010-07-02). "Efficient Total Synthesis of Ammosamide B". Organic Letters. 12 (13): 3112–3114. doi:10.1021/ol101215x. ISSN 1523-7060. PMC 2894265. PMID 20515072.
  34. ^ Hughes, Chambers C.; MacMillan, John B.; Gaudêncio, Susana P.; Fenical, William; La Clair, James J. (2009). "Ammosamides A and B Target Myosin". Angewandte Chemie International Edition. 48 (4): 728–732. doi:10.1002/anie.200804107. ISSN 1521-3773. PMC 2820877. PMID 19097126.
  35. ^ Devraj, Rajesh; Cushman, Mark (1996-01-01). "A Versatile Solid Phase Synthesis of Lavendustin A and Certain Biologically Active Analogs". The Journal of Organic Chemistry. 61 (26): 9368–9373. doi:10.1021/jo961719l. ISSN 0022-3263.
  36. ^ Onoda, Toshihiko; Iinuma, Hironobu; Sasaki, Yumi; Hamada, Masa; Isshiki, Kunio; Naganawa, Hiroshi; Takeuchi, Tomio; Tatsuta, Kuniaki; Umezawa, Kazuo (1989-11-01). "Isolation of a Novel Tyrosine Kinase Inhibitor, Lavendustin A, from Streptomyces griseolavendus". Journal of Natural Products. 52 (6): 1252–1257. doi:10.1021/np50066a009. ISSN 0163-3864. PMID 2614420.
  37. ^ Cushman, Mark; Abbaspour, Aziz; Gupta, Yash Pal (1983-05-01). "Total synthesis of (.+-.)-14-epicorynoline, (.+-.)-corynoline, and (.+-.)-6-oxocorynoline". Journal of the American Chemical Society. 105 (9): 2873–2879. doi:10.1021/ja00347a057. ISSN 0002-7863.
  38. ^ Cushman, Mark; Abbaspour, Aziz; Gupta, Yash Pal (1990-07-01). "Total synthesis of (.+-.)-14-epicorynoline, (.+-.)-corynoline, and (.+-.)-6-oxocorynoline [Erratum to document cited in CA98(21):179711f]". Journal of the American Chemical Society. 112 (15): 5898. doi:10.1021/ja00171a050. ISSN 0002-7863.
  39. ^ "Purdue University Chapter of Sigma Xi Research Award in Science and Engineering".
  40. ^ "Philip S. Portoghese Joint Lectureship".
  41. ^ "Ole Gisvold Lectureship Award in Medicinal Chemistry". 8 September 2015.
  42. ^ "National Academy of Inventors Fellow".
  43. ^ "Highly Prolific Author by the Journal of Medicinal Chemistry".
  44. ^ "Purdue Innovators Hall of Fame".
  45. ^ "University of California San Francisco 150th Anniversary Alumni Excellence Award".
  46. ^ "Webster-Sibilsky Lectureship".
  47. ^ "American Association for the Advancement of Science Fellowship Award" (PDF).
  48. ^ "Chaney Scholar Award for Exceptional Research".
  49. ^ "Purdue Cancer Research Award".
  50. ^ a b "Purdue trustees ratify appointments, honor administrators and athletes, confirm retirement plan change, approve coal purchase". www.purdue.edu. Retrieved 2021-08-27.
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