PMID- 34920311
OWN - NLM
STAT- MEDLINE
DCOM- 20220223
LR  - 20220223
IS  - 1464-3391 (Electronic)
IS  - 0968-0896 (Linking)
VI  - 54
DP  - 2022 Jan 15
TI  - Synthesis of sp(3)-rich chiral bicyclo[3.3.1]nonanes for chemical space expansion 
      and study of biological activities.
PG  - 116561
LID - S0968-0896(21)00569-1 [pii]
LID - 10.1016/j.bmc.2021.116561 [doi]
AB  - Chiral sp(3)-rich bicyclo[3.3.1]nonane scaffolds 10-12 were synthesized as single 
      diastereomers from aldehyde 9, which was prepared from 
      4,4-dimethoxycyclohexa-2,5-dienone through a copper-catalyzed enantioselective 
      reduction. Three different types of intramolecular addition reactions were 
      studied: SmI(2)-mediated reductive cyclization, base-promoted aldol reaction, and 
      one-pot Mannich reaction. We succeeded in introducing three side-chains to 
      scaffold 11 and construct an sp(3)-rich compound library in both enantiomeric 
      variants by simply changing the chirality of the ligands. The biological 
      evaluation revealed that all synthesized compounds exhibited a 
      concentration-dependent inhibition of hypoxia-inducible factor-1 (HIF-1) 
      transcriptional activity, with IC(50) values in the range of 17.2-31.7 microM, 
      whereas their effects on cell viability were varied (IC(50) = 3.5 to > 100 microM). 
      The most active compound 16f inhibits the accumulation of HIF-1alpha protein and mRNA 
      in hypoxia, indicating that it has a mechanism of action distinctly different 
      from other known compounds bearing the common bicyclo[3.3.1]nonane skeleton.
CI  - Copyright (c) 2021 Elsevier Ltd. All rights reserved.
FAU - Ueda, Hiroki
AU  - Ueda H
AD  - School of Life Science and Technology, Tokyo Institute of Technology, 4259 
      Nagatsuta‑cho, Midori‑ku, Yokohama 226‑8501, Japan.
FAU - Wipf, Peter
AU  - Wipf P
AD  - Department of Chemistry, University of Pittsburgh, Pittsburgh, PA 15260, USA. 
      Electronic address: pwipf@pitt.edu.
FAU - Nakamura, Hiroyuki
AU  - Nakamura H
AD  - School of Life Science and Technology, Tokyo Institute of Technology, 4259 
      Nagatsuta‑cho, Midori‑ku, Yokohama 226‑8501, Japan; Laboratory for Chemistry and 
      Life Science, Institute of Innovative Research, Tokyo Institute of Technology, 
      4259 Nagatsuta‑cho, Midori‑ku, Yokohama 226‑8503, Japan. Electronic address: 
      hiro@res.titech.ac.jp.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20211211
PL  - England
TA  - Bioorg Med Chem
JT  - Bioorganic & medicinal chemistry
JID - 9413298
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Bridged Bicyclo Compounds)
RN  - 0 (HIF1A protein, human)
RN  - 0 (Hypoxia-Inducible Factor 1, alpha Subunit)
RN  - 0 (Ligands)
RN  - 0 (RNA, Messenger)
RN  - 0 (bicyclo(3.3.1)nonane)
SB  - IM
MH  - Antineoplastic Agents/chemical synthesis/chemistry/*pharmacology
MH  - Bridged Bicyclo Compounds/chemical synthesis/chemistry/*pharmacology
MH  - Cell Hypoxia/drug effects
MH  - Cell Proliferation/drug effects
MH  - Crystallography, X-Ray
MH  - Dose-Response Relationship, Drug
MH  - Drug Screening Assays, Antitumor
MH  - HeLa Cells
MH  - Humans
MH  - Hypoxia-Inducible Factor 1, alpha Subunit/*antagonists & inhibitors/metabolism
MH  - Ligands
MH  - Models, Molecular
MH  - Molecular Structure
MH  - RNA, Messenger/antagonists & inhibitors/metabolism
MH  - Structure-Activity Relationship
MH  - Tumor Cells, Cultured
OTO - NOTNLM
OT  - Bicyclo[3.3.1]nonane
OT  - Chemical space
OT  - Hypoxia-inducible factor
OT  - Structural diversity
OT  - sp(3)-rich
EDAT- 2021/12/18 06:00
MHDA- 2022/02/24 06:00
CRDT- 2021/12/17 20:21
PHST- 2021/11/18 00:00 [received]
PHST- 2021/12/04 00:00 [revised]
PHST- 2021/12/07 00:00 [accepted]
PHST- 2021/12/18 06:00 [pubmed]
PHST- 2022/02/24 06:00 [medline]
PHST- 2021/12/17 20:21 [entrez]
AID - S0968-0896(21)00569-1 [pii]
AID - 10.1016/j.bmc.2021.116561 [doi]
PST - ppublish
SO  - Bioorg Med Chem. 2022 Jan 15;54:116561. doi: 10.1016/j.bmc.2021.116561. Epub 2021 
      Dec 11.