Microbes use diverse defence strategies that allow them to withstand exposure to a variety of genome invaders such as bacteriophages and plasmids. One such defence strategy is the use of RNA guided endonuclease called CRISPR-associated (Cas) 9 protein. The Cas9 protein, derived from type II CRISPR/Cas system, has been adapted as a versatile tool for genome targeting and engineering due to its simplicity and high efficiency over the earlier tools such as ZFNs and TALENs. With recent advancements, CRISPR/Cas9 technology has emerged as a revolutionary tool for modulating the genome in living cells and inspires innovative translational applications in different fields. In this paper we review the developments and its potential uses in the CRISPR/Cas9 technology as well as recent advancements in genome engineering using CRISPR/Cas9.
A series
of 1,3,4-oxadiazole tethered capsaicin derivatives was
prepared by using one point modification at the vanillyl-hydroxyl
group of capsaicin. All the prepared capsaicinoids were evaluated
for their antiproliferative activity against NCI-60 human cancer cell
lines at 10 μM. Among the compounds tested, compound 20a exhibited good cytotoxic activity against HCT-116, NCI-H460, and
SKOV3 cell lines with IC50 8.55 μΜ, 5.41 μΜ,
and 6.4 μΜ, respectively, compared to the parent natural
product capsaicin. Further on, it significantly inhibited the colony
formation in NCI-H460 in a dose dependent manner and enhanced the
ROS effect. It also caused cell arrest at the S phase and induced
apoptosis via suppressing the Pro parp marker. Compound 20a exhibited an antimigratory property and suppressed the expression
of the VEGF marker in a dose dependent manner. Furthermore, compound 20a also suppressed the effects of the p-Erk, p-p38, and P-CNA
makers. In silico studies supported the interaction
of this class of compounds with the VEGFR2 protein.
A series of novel
1,2,3-triazole derivatives of capsaicin
and its
structural isomer (new natural product hybrid capsaicinoid) were synthesized
by exploiting one-/two-point modification of capsaicin without altering
the amide linkage (neck). The newly synthesized compounds were screened
for their antiproliferative activity against an NCI panel of 60 cancer
cell lines at a single dose of 10 μM. Most of the compounds
have demonstrated reduced growth between 55 and 95%, whereas capsaicin
(
10
) has shown reduced growth between 0 and 24%. Compounds
showing more than 50% growth inhibition were further evaluated for
the IC
50
value. Among the cell lines tested, lung cancer
cell lines (A549, NCI-H460) were found to be more susceptible toward
most of the synthesized compounds. Compounds
14g
and
14j
demonstrated good antiproliferative activity in NCI-H460
with IC
50
values of 6.65 and 5.55 μM, respectively,
while compounds
18b
,
18c
,
18f
, and
18m
demonstrated potential antiproliferative activity
in A549 cell lines with IC
50
values ranging between 2.9
and 10.5 μM. Among the compounds, compound
18f
was
found to demonstrate the best activity with an IC
50
value
of 2.91 μM against A549. Furthermore,
18f
induces
cell cycle arrest at the S-phase and disrupts the mitochondrial membrane
potential, reducing cell migration potential by inducing cellular
apoptosis and higher ROS generation along with a decrease in mitochondrial
membrane potential in addition to surface and nuclear morphological
alterations such as a reduction in the number and shrinkage of cells
coupled with nuclear blabbing indicating the sign of apoptosis of
A549 non-small cell lung cancer cell lines. Compound
18f
has emerged as a lead molecule and may serve as a template for further
discovery of capsaicinoid scaffolds.
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