Title:Tropolones and Thailandepsin B as Lead-like Natural Compounds in the
Development of Potent and Selective Histone Deacetylase Inhibitors
Volume: 24
Issue: 9
Author(s): Dilipkumar Pal*Padum Lal
Affiliation:
- Department of Pharmaceutical Sciences, Guru Ghasidash Vishwavidyalaya (A Central University), Bilaspur, C.G.,
495 009, India
Keywords:
Tropolone, HDAC, isozyme-selectivity, thujaplicin, metalloenzyme, natural product, HDAC inhibitor, thailandepsin B, synthesis, biosynthesis, bacterial products, antiproliferative activities.
Abstract:
Background: Tropolone and thailandepsin B are naturally occurring substances that are
primarily isolated from fungi and plants, although they can also be found in certain bacteria.
Tropolones belong to an important class of aromatic compounds with a seven-membered nonbenzenoid
ring structure. Thailandepsins are a group of natural products that were initially discovered
in the culture broth of the Gram-negative bacterium Burkholderia thailandensis. Tropolonebased
structures have been identified in over 200 natural compounds, ranging from simple
tropolone derivatives to complex multicyclic systems like pycnidione and pyrerubrine A.
These natural compounds exhibit a diverse range of pharmacological effects, including antibacterial,
antifungal, insecticidal, phytotoxic, anti-inflammatory, antimitotic, anti-diabetic, enzyme inhibitory,
anticancer, cytoprotective, and ROS scavenging properties. It is worth noting that thujaplicane,
a compound similar to tropolone, displays all of the listed biological activities except for antimitotic
action, which has only been observed in one natural tropolone compound, colchicine.
Tropolone can be synthesized from commercially available seven-membered rings or derived
through various cyclization and cycloaddition reactions. Thailandepsin B, on the other hand, can be
synthesized by macro-lactonization of the corresponding secoacid, followed by the formation of internal
disulfide bonds. It is important to mention that thailandepsin B exhibits different selective inhibition
profiles compared to FK228.
Objective: We investigated the HDAC inhibitory activity of the Tropolones and Thailandepsin B
and discussed the biosynthesis of the naturally occurring compounds and their synthetic scheme.
Results and Conclusion: It has been observed that Tropolone derivatives act as isoenzyme-selective
inhibitors of proven anticancer drug targets, histone deacetylases (HDACs). Some monosubstituted
tropolones show remarkable levels of selectivity for HDAC2 and strongly inhibit the growth
of T-lymphocyte cell lines. And Thailandepsins have different selective inhibition profiles than
FK228. They exhibit comparable inhibitory activities to FK228 against human HDAC1, HDAC2,
HDAC3, HDAC6, HDAC7, and HDAC9, but less potent inhibitory activities than FK228 toward
HDAC4 and HDAC8, the latter of which may be useful. Thailandepsins possess potent cytotoxic
activities toward some types of cell lines.
