TY - JOUR
T1 - Model studies towards prodrugs of the glutamine antagonist 6-diazo-5-oxo-L-norleucine (DON) containing a diazo precursor
AU - Gao, Run Duo
AU - Hin, Niyada
AU - Prchalová, Eva
AU - Pal, Arindom
AU - Lam, Jenny
AU - Rais, Rana
AU - Slusher, Barbara S.
AU - Tsukamoto, Takashi
N1 - Funding Information:
The authors of this manuscript have been supported by NIH grants P30MH075673 (B.S.S) and R01NS103927 (B.S.S.). The authors are also grateful for the support provided by the Bloomberg-Kimmel Institute for Cancer Immunotherapy at Johns Hopkins.
Funding Information:
The authors of this manuscript have been supported by NIH grants P30MH075673 (B.S.S) and R01NS103927 (B.S.S.). The authors are also grateful for the support provided by the Bloomberg-Kimmel Institute for Cancer Immunotherapy at Johns Hopkins.
Publisher Copyright:
© 2021 Elsevier Ltd
PY - 2021/10/15
Y1 - 2021/10/15
N2 - Two distinct diazo precursors, imidazotetrazine and nitrous amide, were explored as promoieties in designing prodrugs of 6-diazo-5-oxo-l-norleucine (DON), a glutamine antagonist. As a model for an imidazotetrazine-based prodrug, we synthesized (S)-2-acetamido-6-(8-carbamoyl-4-oxoimidazo[5,1-d][1,2,3,5]tetrazin-3(4H)-yl)-5-oxohexanoic acid (4) containing the entire scaffold of temozolomide, a precursor of the DNA-methylating agent clinically approved for the treatment of glioblastoma multiforme. For a nitrous amide-based prodrug, we synthesized 2-acetamido-6-(((benzyloxy)carbonyl)(nitroso)amino)-5-oxohexanoic acid (5) containing a N-nitrosocarbamate group, which can be converted to a diazo moiety via a mechanism similar to that of streptozotocin, a clinically approved diazomethane-releasing drug containing an N-nitrosourea group. Preliminary characterization confirmed formation of N-acetyl DON (6), also known as duazomycin A, from compound 4 in a pH-dependent manner while compound 5 did not exhibit sufficient stability to allow further characterization. Taken together, our model studies suggest that further improvements are needed to translate this prodrug approach into glutamine antagonist-based therapy.
AB - Two distinct diazo precursors, imidazotetrazine and nitrous amide, were explored as promoieties in designing prodrugs of 6-diazo-5-oxo-l-norleucine (DON), a glutamine antagonist. As a model for an imidazotetrazine-based prodrug, we synthesized (S)-2-acetamido-6-(8-carbamoyl-4-oxoimidazo[5,1-d][1,2,3,5]tetrazin-3(4H)-yl)-5-oxohexanoic acid (4) containing the entire scaffold of temozolomide, a precursor of the DNA-methylating agent clinically approved for the treatment of glioblastoma multiforme. For a nitrous amide-based prodrug, we synthesized 2-acetamido-6-(((benzyloxy)carbonyl)(nitroso)amino)-5-oxohexanoic acid (5) containing a N-nitrosocarbamate group, which can be converted to a diazo moiety via a mechanism similar to that of streptozotocin, a clinically approved diazomethane-releasing drug containing an N-nitrosourea group. Preliminary characterization confirmed formation of N-acetyl DON (6), also known as duazomycin A, from compound 4 in a pH-dependent manner while compound 5 did not exhibit sufficient stability to allow further characterization. Taken together, our model studies suggest that further improvements are needed to translate this prodrug approach into glutamine antagonist-based therapy.
KW - 6-Diazo-5-oxo-L-norleucine
KW - Prodrug
KW - α-Diazoketone
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U2 - 10.1016/j.bmcl.2021.128321
DO - 10.1016/j.bmcl.2021.128321
M3 - Article
C2 - 34400301
AN - SCOPUS:85114134176
SN - 0960-894X
VL - 50
JO - Bioorganic and Medicinal Chemistry Letters
JF - Bioorganic and Medicinal Chemistry Letters
M1 - 128321
ER -