PMID- 31246453
OWN - NLM
STAT- MEDLINE
DCOM- 20200701
LR  - 20200701
IS  - 1520-6904 (Electronic)
IS  - 0022-3263 (Linking)
VI  - 84
IP  - 14
DP  - 2019 Jul 19
TI  - Progress toward the Total Synthesis of Lymphostins: Preparation of a 
      Functionalized Tetrahydropyrrolo[4,3,2-de]quinoline and Unusual Oxidative 
      Dimerization.
PG  - 9339-9343
LID - 10.1021/acs.joc.9b01041 [doi]
AB  - The lymphostins are a family of closely related pyrrolo[4,3,2-de]quinoline 
      natural products produced by Streptomyces and Salinispora actinobacteria. 
      Neolymphostin A was recently shown to strongly inhibit phosphoinositide 3-kinase 
      (PI3K) and the mammalian target of rapamycin (mTOR) in a covalent manner via 
      conjugation to a catalytic lysine residue in the ATP-binding pocket of the 
      enzymes, making this metabolite the first reported covalent kinase inhibitor from 
      a bacterium. A flexible and efficient synthetic route toward these alkaloids 
      would allow for improvements in their solubility, stability, and selectivity and 
      help to deliver a viable drug candidate. We have since established a short 
      synthesis to methyl 
      8-bromo-1,3,4,5-tetrahydropyrrolo[4,3,2-de]quinoline-4-carboxylate via a 
      conjugate addition/intramolecular Ullman reaction sequence. However, attempts to 
      oxidize this intermediate to the pyrrolo[4,3,2-de]quinoline characteristic of the 
      lymphostins resulted in formation of either a 
      2-oxo-1,2-dihydropyrrolo[4,3,2-de]quinoline or an unusual N,C-linked 
      tetrahydropyrroloquinoline-pyrroloquinoline heterodimer. We expect that key 
      modifications to the tetrahydropyrroloquinoline intermediate prior to oxidation 
      should prevent these side reactions and pave the way for the completion of the 
      synthesis.
FAU - Seiler, Grant S
AU  - Seiler GS
AD  - Center for Marine Biotechnology and Biomedicine, Scripps Institution of 
      Oceanography , University of California, San Diego , La Jolla , California 92093 
      , United States.
AD  - Department of Chemistry and Biochemistry , University of California, San Diego , 
      La Jolla , California 92093 , United States.
FAU - Hughes, Chambers C
AU  - Hughes CC
AUID- ORCID: 0000-0002-7000-6438
AD  - Center for Marine Biotechnology and Biomedicine, Scripps Institution of 
      Oceanography , University of California, San Diego , La Jolla , California 92093 
      , United States.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20190627
PL  - United States
TA  - J Org Chem
JT  - The Journal of organic chemistry
JID - 2985193R
RN  - 0 (Quinolines)
SB  - IM
MH  - Molecular Structure
MH  - Oxidation-Reduction
MH  - Quinolines/*chemical synthesis
EDAT- 2019/06/28 06:00
MHDA- 2020/07/02 06:00
CRDT- 2019/06/28 06:00
PHST- 2019/06/28 06:00 [pubmed]
PHST- 2020/07/02 06:00 [medline]
PHST- 2019/06/28 06:00 [entrez]
AID - 10.1021/acs.joc.9b01041 [doi]
PST - ppublish
SO  - J Org Chem. 2019 Jul 19;84(14):9339-9343. doi: 10.1021/acs.joc.9b01041. Epub 2019 
      Jun 27.