PMID- 21361357
OWN - NLM
STAT- MEDLINE
DCOM- 20110923
LR  - 20141120
IS  - 1520-5010 (Electronic)
IS  - 0893-228X (Linking)
VI  - 24
IP  - 4
DP  - 2011 Apr 18
TI  - Characterization of short-lived electrophilic metabolites of the anticancer agent 
      laromustine (VNP40101M).
PG  - 568-78
LID - 10.1021/tx100453t [doi]
AB  - Laromustine (VNP40101M; 1,2-bis(methylsulfonyl)-1-(2-chloroethyl)-2-(methylamino) 
      carbonylhydrazine) is a novel sulfonylhydrazine alkylating agent. Phase 1 
      metabolism of laromustine was reported recently and showed that laromustine 
      undergoes rearrangement, dehalogenation, and hydrolysis at physiological pH to 
      form active moieties. (1) A mechanism for the rearrangement was proposed on the 
      basis of fragmentation ions. (1) (,) (2) In this article, we report the phase II 
      conjugates of VNP40101M and VNP4090CE which were formed after incubation of 
      VNP40101M or VNP4090CE with pooled human liver microsomes (HLM) and cofactors 
      nicotinamide adenine dinucleotide phosphate (NADPH), glutathione (GSH), 
      N-acetylecysteine (NAC), and cysteine (CYS). Eight novel phase II conjugates (M-1 
      to M-8) were identified and characterized by hydrogen-deuterium exchange (H-D), 
      stable isotope ((13)C-labeled VNP40101M), and MS(n) experiments. M-4 and M-5 were 
      further confirmed by nuclear magnetic resonance spectroscopy (NMR). The 
      short-lived CH(3)SO(2)CH(2)CH(2)-, methylformamide and CH(3)SO(2)NHN horizontal lineCHCH(2)- 
      moieties were generated from VNP40101M. The reactive intermediates 
      CH(3)SO(2)CH(2)CH(2)- and methylformamide formed conjugates with GSH, CYS, and 
      NAC. The CH(3)SO(2)NHN horizontal lineCHCH(2)- moiety formed conjugates with GSH and NAC. M-2, 
      M-4, and M-6 were only detected from the incubation of VNP40101M because 
      VNP4090CE does not contain a methylformamide group. All other conjugates were 
      formed by both VNP40101M and VNP4090CE. The in vitro studies found that VNP40101M 
      and VNP4090CE undergo activation in human liver microsomes. The results from this 
      study showed that laromustine produces several reactive intermediates that may 
      play a role in the toxicities seen in the clinical trials.
FAU - Nassar, A-E F
AU  - Nassar AE
AD  - Department of Chemistry, Brandeis University , 415 South Street, Waltham, MA 
      02453, United States. NassarAL@aol.com
FAU - King, I
AU  - King I
FAU - Du, J
AU  - Du J
LA  - eng
PT  - Journal Article
DEP - 20110325
PL  - United States
TA  - Chem Res Toxicol
JT  - Chemical research in toxicology
JID - 8807448
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Carbon Isotopes)
RN  - 0 (Hydrazines)
RN  - 0 (Sulfonamides)
RN  - 0 (VNP-4090-CE)
RN  - 14J2G0U3NQ (laromustine)
RN  - 53-59-8 (NADP)
RN  - GAN16C9B8O (Glutathione)
RN  - K848JZ4886 (Cysteine)
RN  - WYQ7N0BPYC (Acetylcysteine)
SB  - IM
MH  - Acetylcysteine/chemistry
MH  - Antineoplastic Agents/chemistry/*metabolism/therapeutic use
MH  - Carbon Isotopes/chemistry
MH  - Chromatography, High Pressure Liquid
MH  - Cysteine/chemistry
MH  - Glutathione/chemistry
MH  - Humans
MH  - Hydrazines/chemistry/*metabolism/therapeutic use
MH  - Magnetic Resonance Spectroscopy
MH  - Microsomes, Liver/metabolism
MH  - NADP/chemistry
MH  - Neoplasms/drug therapy
MH  - Spectrometry, Mass, Electrospray Ionization
MH  - Sulfonamides/chemistry/*metabolism/therapeutic use
EDAT- 2011/03/03 06:00
MHDA- 2011/09/29 06:00
CRDT- 2011/03/03 06:00
PHST- 2011/03/03 06:00 [entrez]
PHST- 2011/03/03 06:00 [pubmed]
PHST- 2011/09/29 06:00 [medline]
AID - 10.1021/tx100453t [doi]
PST - ppublish
SO  - Chem Res Toxicol. 2011 Apr 18;24(4):568-78. doi: 10.1021/tx100453t. Epub 2011 Mar 
      25.