42 research outputs found
Discovery of Novel KRAS-PDEδ Inhibitors by Fragment-Based Drug Design
Targeting
KRAS-PDEδ protein–protein interactions with
small molecules represents a promising opportunity for developing
novel antitumor agents. However, current KRAS-PDEδ inhibitors
are limited by poor cellular antitumor potency and the druggability
of the target remains to be validated by new inhibitors. To tackle
these challenges, herein, novel, highly potent KRAS-PDEδ inhibitors
were identified by fragment-based drug design, providing promising
lead compounds or chemical probes for investigating the biological
functions and druggability of KRAS-PDEδ interaction
Discovery of Novel KRAS-PDEδ Inhibitors by Fragment-Based Drug Design
Targeting
KRAS-PDEδ protein–protein interactions with
small molecules represents a promising opportunity for developing
novel antitumor agents. However, current KRAS-PDEδ inhibitors
are limited by poor cellular antitumor potency and the druggability
of the target remains to be validated by new inhibitors. To tackle
these challenges, herein, novel, highly potent KRAS-PDEδ inhibitors
were identified by fragment-based drug design, providing promising
lead compounds or chemical probes for investigating the biological
functions and druggability of KRAS-PDEδ interaction
Design of Evodiamine–Glucose Conjugates with Improved <i>In Vivo</i> Antitumor Activity
Natural
product evodiamine is a multitargeting antitumor
lead compound.
However, clinical development of evodiamine derivatives was hampered
by poor water solubility and limited in vivo antitumor
potency. Herein, a series of evodiamine–glucose conjugates
were designed by additional targeting glucose transporter-1 (GLUT1).
Compared with the lead compound, conjugate 8 exhibited
obvious enhancement in water solubility and in vivo antitumor efficacy. Furthermore, the effect of GLUT1 targeting also
led to lower cytotoxicity to normal cells. Antitumor mechanism studies
manifested that conjugate 8 acted by Top1/Top2 dual inhibition,
apoptosis induction, and G2/M cell cycle arrest, which
selectively targeted tumor cells with a high expression level of GLUT1.
Thus, evodiamine–glucose conjugates showed promising features
as potential antitumor agents
Design of Evodiamine–Glucose Conjugates with Improved <i>In Vivo</i> Antitumor Activity
Natural
product evodiamine is a multitargeting antitumor
lead compound.
However, clinical development of evodiamine derivatives was hampered
by poor water solubility and limited in vivo antitumor
potency. Herein, a series of evodiamine–glucose conjugates
were designed by additional targeting glucose transporter-1 (GLUT1).
Compared with the lead compound, conjugate 8 exhibited
obvious enhancement in water solubility and in vivo antitumor efficacy. Furthermore, the effect of GLUT1 targeting also
led to lower cytotoxicity to normal cells. Antitumor mechanism studies
manifested that conjugate 8 acted by Top1/Top2 dual inhibition,
apoptosis induction, and G2/M cell cycle arrest, which
selectively targeted tumor cells with a high expression level of GLUT1.
Thus, evodiamine–glucose conjugates showed promising features
as potential antitumor agents
Design of Evodiamine–Glucose Conjugates with Improved <i>In Vivo</i> Antitumor Activity
Natural
product evodiamine is a multitargeting antitumor
lead compound.
However, clinical development of evodiamine derivatives was hampered
by poor water solubility and limited in vivo antitumor
potency. Herein, a series of evodiamine–glucose conjugates
were designed by additional targeting glucose transporter-1 (GLUT1).
Compared with the lead compound, conjugate 8 exhibited
obvious enhancement in water solubility and in vivo antitumor efficacy. Furthermore, the effect of GLUT1 targeting also
led to lower cytotoxicity to normal cells. Antitumor mechanism studies
manifested that conjugate 8 acted by Top1/Top2 dual inhibition,
apoptosis induction, and G2/M cell cycle arrest, which
selectively targeted tumor cells with a high expression level of GLUT1.
Thus, evodiamine–glucose conjugates showed promising features
as potential antitumor agents
Design of Evodiamine–Glucose Conjugates with Improved <i>In Vivo</i> Antitumor Activity
Natural
product evodiamine is a multitargeting antitumor
lead compound.
However, clinical development of evodiamine derivatives was hampered
by poor water solubility and limited in vivo antitumor
potency. Herein, a series of evodiamine–glucose conjugates
were designed by additional targeting glucose transporter-1 (GLUT1).
Compared with the lead compound, conjugate 8 exhibited
obvious enhancement in water solubility and in vivo antitumor efficacy. Furthermore, the effect of GLUT1 targeting also
led to lower cytotoxicity to normal cells. Antitumor mechanism studies
manifested that conjugate 8 acted by Top1/Top2 dual inhibition,
apoptosis induction, and G2/M cell cycle arrest, which
selectively targeted tumor cells with a high expression level of GLUT1.
Thus, evodiamine–glucose conjugates showed promising features
as potential antitumor agents
Discovery of Janus Kinase 2 (JAK2) and Histone Deacetylase (HDAC) Dual Inhibitors as a Novel Strategy for the Combinational Treatment of Leukemia and Invasive Fungal Infections
Clinically, leukemia patients often
suffer from the limited efficacy
of chemotherapy and high risks of infection by invasive fungal pathogens.
Herein, a novel therapeutic strategy was developed in which a small
molecule can simultaneously treat leukemia and invasive fungal infections
(IFIs). Novel Janus kinase 2 (JAK2) and histone deacetylase (HDAC)
dual inhibitors were identified to possess potent anti-proliferative
activity toward hematological cell lines and excellent synergistic
effects with fluconazole to treat resistant <i>Candida albicans</i> infections. In particular, compound <b>20a</b>, a highly active
and selective JAK2/HDAC6 dual inhibitor, showed excellent in vivo
antitumor efficacy in several acute myeloid leukemia (AML) models
and synergized with fluconazole for the treatment of resistant <i>C. albicans</i> infections. This study highlights the therapeutic
potential of JAK2/HDAC dual inhibitors in treating AML and IFIs and
provides an efficient strategy for multitargeting drug discovery
Dual NAMPT/HDAC Inhibitors as a New Strategy for Multitargeting Antitumor Drug Discovery
Novel dual nicotinamide phosphoribosyltransferase
(NAMPT) and histone deacetylase (HDAC) inhibitors were designed by
a pharmacophore fusion approach. The thiazolocarboxamide inhibitors
were highly active for both targets. In particular, compound <b>7f</b> (NAMPT IC<sub>50</sub> = 15 nM, HDAC1 IC<sub>50</sub> =
2 nM) showed potent <i>in vivo</i> antitumor efficacy in
the HCT116 xenograft model. The study offers a new strategy for multitarget
antitumor drug discovery by simultaneously acting on cancer metabolism
and epigenetics
Discovery of New Tricyclic Oxime Sampangine Derivatives as Potent Antifungal Agents for the Treatment of Cryptococcosis and Candidiasis
Cryptococcus neoformans (C. neoformans) and Candida albicans (C. albicans) are classified as the
critical priority groups among the pathogenic fungi, highlighting
the urgent need for developing more effective antifungal therapies.
On the basis of antifungal natural product sampangine, herein, a series
of tricyclic oxime and oxime ether derivatives were designed. Among
them, compound WZ-2 showed excellent inhibitory activity
against C. neoformans (MIC80 = 0.016 ÎĽg/mL) and synergized with fluconazole to treat resistant C. albicans (FICI = 0.078). Interestingly, compound WZ-2 effectively inhibited virulence factors (e.g., capsule,
biofilm, and yeast-to-hypha morphological transition), suggesting
the potential to overcome drug resistance. In a mouse model of cryptococcal
meningitis, compound WZ-2 (5 mg/kg) effectively reduced
the brain C. neoformans H99 burden.
Furthermore, compound WZ-2 alone and its combination
with fluconazole also significantly reduced the kidney burden of the
drug-resistant strain (0304103) and sensitive strain (SC5314) of C. albicans
One-Pot Synthesis of Deuterated Aldehydes from Arylmethyl Halides
A facile, one-pot
approach for synthesizing deuterated aldehydes
from arylmethyl halides was developed using D<sub>2</sub>O as the
deuterium source. The efficient process is realized by a sequence
of formation, H/D exchange, and oxidation of pyridinium salt intermediates.
The mild and air-compatible reaction conditions enable efficient synthesis
of diverse deuterated aldehydes with high deuterium incorporation