Synthesis and evaluation of analogs of 5'-(((Z)-4-amino-2-butenyl)methylamino)-5'-deoxyadenosine (MDL 73811, or AbeAdo) - An inhibitor of S-adenosylmethionine decarboxylase with antitrypanosomal activity

Anthony J. Brockway, Oleg A. Volkov, Casey C. Cosner, Karen S. MacMillan, Stephen A. Wring, Thomas E. Richardson, Michael Peel, Margaret A. Phillips, Jef K. De Brabander

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

We describe our efforts to improve the pharmacokinetic properties of a mechanism-based suicide inhibitor of the polyamine biosynthetic enzyme S-adenosylmethionine decarboxylase (AdoMetDC), essential for the survival of the eukaryotic parasite Trypanosoma brucei responsible for Human African Trypanosomiasis (HAT). The lead compound, 5'-(((. Z)-4-amino-2-butenyl)methylamino)-5'-deoxyadenosine (1, also known as MDL 73811, or AbeAdo), has curative efficacy at a low dosage in a hemolymphatic model of HAT but displayed no demonstrable effect in a mouse model of the CNS stage of HAT due to poor blood-brain barrier permeation. Therefore, we prepared and evaluated an extensive set of analogs with modifications in the aminobutenyl side chain, the 5'-amine, the ribose, and the purine fragments. Although we gained valuable structure-activity insights from this comprehensive dataset, we did not gain traction on improving the prospects for CNS penetration while retaining the potent antiparasitic activity and metabolic stability of the lead compound 1.

Original languageEnglish (US)
JournalBioorganic and Medicinal Chemistry
DOIs
StateAccepted/In press - 2017

Fingerprint

Adenosylmethionine Decarboxylase
African Trypanosomiasis
Lead compounds
Antiparasitic Agents
Trypanosoma brucei brucei
Pharmacokinetics
Ribose
Polyamines
Traction
Blood-Brain Barrier
Permeation
Suicide
Amines
Parasites
Enzymes
MDL 73811
Lead

Keywords

  • Antitrypanosomal
  • Human African Trypanosomiasis
  • Metabolism
  • Permeability
  • S-adenosylmethionine decarboxylase
  • Structure-activity relationship

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

Cite this

Synthesis and evaluation of analogs of 5'-(((Z)-4-amino-2-butenyl)methylamino)-5'-deoxyadenosine (MDL 73811, or AbeAdo) - An inhibitor of S-adenosylmethionine decarboxylase with antitrypanosomal activity. / Brockway, Anthony J.; Volkov, Oleg A.; Cosner, Casey C.; MacMillan, Karen S.; Wring, Stephen A.; Richardson, Thomas E.; Peel, Michael; Phillips, Margaret A.; De Brabander, Jef K.

In: Bioorganic and Medicinal Chemistry, 2017.

Research output: Contribution to journalArticle

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