10 research outputs found
Recent Advances in the Development of Non-PIKKs Targeting Small Molecule Inhibitors of DNA Double-Strand Break Repair
The vast majority of cancer patients receive DNA-damaging drugs or ionizing radiation (IR) during their course of treatment, yet the efficacy of these therapies is tempered by DNA repair and DNA damage response (DDR) pathways. Aberrations in DNA repair and the DDR are observed in many cancer subtypes and can promote de novo carcinogenesis, genomic instability, and ensuing resistance to current cancer therapy. Additionally, stalled or collapsed DNA replication forks present a unique challenge to the double-strand DNA break (DSB) repair system. Of the various inducible DNA lesions, DSBs are the most lethal and thus desirable in the setting of cancer treatment. In mammalian cells, DSBs are typically repaired by the error prone non-homologous end joining pathway (NHEJ) or the high-fidelity homology directed repair (HDR) pathway. Targeting DSB repair pathways using small molecular inhibitors offers a promising mechanism to synergize DNA-damaging drugs and IR while selective inhibition of the NHEJ pathway can induce synthetic lethality in HDR-deficient cancer subtypes. Selective inhibitors of the NHEJ pathway and alternative DSB-repair pathways may also see future use in precision genome editing to direct repair of resulting DSBs created by the HDR pathway. In this review, we highlight the recent advances in the development of inhibitors of the non-phosphatidylinositol 3-kinase-related kinases (non-PIKKs) members of the NHEJ, HDR and minor backup SSA and alt-NHEJ DSB-repair pathways. The inhibitors described within this review target the non-PIKKs mediators of DSB repair including Ku70/80, Artemis, DNA Ligase IV, XRCC4, MRN complex, RPA, RAD51, RAD52, ERCC1-XPF, helicases, and DNA polymerase θ. While the DDR PIKKs remain intensely pursued as therapeutic targets, small molecule inhibition of non-PIKKs represents an emerging opportunity in drug discovery that offers considerable potential to impact cancer treatment
I<sub>2</sub>/Aqueous TBHP-Catalyzed Coupling of Amides with Methylarenes/Aldehydes/Alcohols: Metal-Free Synthesis of Imides
We
present a metal-free method for the synthesis of imides by the
direct coupling of NH-amides with methylarenes under iodine/aqueous
TBHP conditions. The optimized conditions worked very well with benzaldehydes
and benzyl alcohol and furnished the corresponding imides in good
to excellent yields. A series of control and radical scavenger experiments
were also performed, which suggested the involvement of radical pathways.
The labeling experiment in the presence of <sup>18</sup>O-labeled
H<sub>2</sub>O suggested water as a source of oxygen in the imides
Metal-Free Approach for the Synthesis of <i>N</i>‑Aryl Sulfoximines via Aryne Intermediate
A metal-free
and operationally simple <i>N</i>-arylation
of <i>NH</i>-sulfoximines with aryne precursors is reported.
Transition metal-free reaction conditions and shorter reaction times
are the highlights of the present method. The mild optimized condition
was also found to be suitable with enantiopure substrates
Metal-free Cross-Dehydrogenative Coupling of <i>HN</i>-azoles with α‑C(sp<sup>3</sup>)‑H Amides via C–H Activation and Its Mechanistic and Application Studies
A metal-free
one step coupling reaction between various <i>N</i>-azole
rings and diverse α-CÂ(sp<sup>3</sup>)-H containing
amides has been developed under oxidative reaction conditions. Commercially
available tetrabutyl ammonium iodide (TBAI) in the presence of terbutylhydroperoxide
(TBHP), under neat reaction condition, efficiently catalyzed the coupling.
Various azole types, such as 1<i>H</i>-benzotriazoles, 1<i>H</i>-1,2,3-triazoles, 1<i>H</i>-1,2,4-triazoles,
1<i>H</i>-tetrazoles, 1<i>H</i>-pyrazoles, and
1<i>H</i>-benzimidazoles, and α-CÂ(sp<sup>3</sup>)-H
containing amides, such as <i>N</i>,<i>N</i>-dimethylacetamide, <i>N</i>,<i>N</i>-dimethylbenzamide, <i>N</i>-methylacetamide, <i>N</i>,<i>N</i>-diethylacetamide, <i>N</i>-methylpyrrolidine, and pyrrolidine-2-one, were successfully
employed for the coupling. A series of designed and controlled experiments
were also performed in order to study the involvement of the different
intermediates. Based on the evidence, a plausible mechanism is also
proposed. These novel, simple, rapid, attractive, and straightforward
transformations open the way of the construction of novel highly functionalized <i>N</i>-azoles via direct covalent N–H bond transformations
onto N–C bonds. This approach allows to the synthesis of complex
molecules requiring number of steps using classical synthetic ways.
In addition, the range of α-CÂ(sp<sup>3</sup>)-H containing amide
substrates is virtually unlimited highlighting the potential value
of this simple system for the construction of complex heterocyclic
molecules, such as fused azoles derivatives
Metal-free Cross-Dehydrogenative Coupling of <i>HN</i>-azoles with α‑C(sp<sup>3</sup>)‑H Amides via C–H Activation and Its Mechanistic and Application Studies
A metal-free
one step coupling reaction between various <i>N</i>-azole
rings and diverse α-CÂ(sp<sup>3</sup>)-H containing
amides has been developed under oxidative reaction conditions. Commercially
available tetrabutyl ammonium iodide (TBAI) in the presence of terbutylhydroperoxide
(TBHP), under neat reaction condition, efficiently catalyzed the coupling.
Various azole types, such as 1<i>H</i>-benzotriazoles, 1<i>H</i>-1,2,3-triazoles, 1<i>H</i>-1,2,4-triazoles,
1<i>H</i>-tetrazoles, 1<i>H</i>-pyrazoles, and
1<i>H</i>-benzimidazoles, and α-CÂ(sp<sup>3</sup>)-H
containing amides, such as <i>N</i>,<i>N</i>-dimethylacetamide, <i>N</i>,<i>N</i>-dimethylbenzamide, <i>N</i>-methylacetamide, <i>N</i>,<i>N</i>-diethylacetamide, <i>N</i>-methylpyrrolidine, and pyrrolidine-2-one, were successfully
employed for the coupling. A series of designed and controlled experiments
were also performed in order to study the involvement of the different
intermediates. Based on the evidence, a plausible mechanism is also
proposed. These novel, simple, rapid, attractive, and straightforward
transformations open the way of the construction of novel highly functionalized <i>N</i>-azoles via direct covalent N–H bond transformations
onto N–C bonds. This approach allows to the synthesis of complex
molecules requiring number of steps using classical synthetic ways.
In addition, the range of α-CÂ(sp<sup>3</sup>)-H containing amide
substrates is virtually unlimited highlighting the potential value
of this simple system for the construction of complex heterocyclic
molecules, such as fused azoles derivatives
Metal-free Cross-Dehydrogenative Coupling of <i>HN</i>-azoles with α‑C(sp<sup>3</sup>)‑H Amides via C–H Activation and Its Mechanistic and Application Studies
A metal-free
one step coupling reaction between various <i>N</i>-azole
rings and diverse α-CÂ(sp<sup>3</sup>)-H containing
amides has been developed under oxidative reaction conditions. Commercially
available tetrabutyl ammonium iodide (TBAI) in the presence of terbutylhydroperoxide
(TBHP), under neat reaction condition, efficiently catalyzed the coupling.
Various azole types, such as 1<i>H</i>-benzotriazoles, 1<i>H</i>-1,2,3-triazoles, 1<i>H</i>-1,2,4-triazoles,
1<i>H</i>-tetrazoles, 1<i>H</i>-pyrazoles, and
1<i>H</i>-benzimidazoles, and α-CÂ(sp<sup>3</sup>)-H
containing amides, such as <i>N</i>,<i>N</i>-dimethylacetamide, <i>N</i>,<i>N</i>-dimethylbenzamide, <i>N</i>-methylacetamide, <i>N</i>,<i>N</i>-diethylacetamide, <i>N</i>-methylpyrrolidine, and pyrrolidine-2-one, were successfully
employed for the coupling. A series of designed and controlled experiments
were also performed in order to study the involvement of the different
intermediates. Based on the evidence, a plausible mechanism is also
proposed. These novel, simple, rapid, attractive, and straightforward
transformations open the way of the construction of novel highly functionalized <i>N</i>-azoles via direct covalent N–H bond transformations
onto N–C bonds. This approach allows to the synthesis of complex
molecules requiring number of steps using classical synthetic ways.
In addition, the range of α-CÂ(sp<sup>3</sup>)-H containing amide
substrates is virtually unlimited highlighting the potential value
of this simple system for the construction of complex heterocyclic
molecules, such as fused azoles derivatives
Cross-Dehydrogenative Coupling of Azoles with α‑C(sp<sup>3</sup>)–H of Ethers and Thioethers under Metal-Free Conditions: Functionalization of H–N Azoles via C–H Activation
A metal-free cross-dehydrogenative
coupling method for the synthesis
of <i>N</i>-substituted azoles has been developed. The TBAI/TBHP
system catalyzed the coupling of azoles with ethers and thioethers
via α-CÂ(sp<sup>3</sup>)–H activation. Under the optimized
conditions, a diverse range of un/substituted azoles such as 1<i>H</i>-benzimidazole, 9<i>H</i>-purine, 1<i>H</i>-benzotriazole, 1<i>H</i>-1,2,3-triazole, 1<i>H</i>-1,2,4-triazole, and 1<i>H</i>-pyrazole were successfully
employed for coupling with various ethers and thioethers such as tetrahydrofuran,
tetrahydropyran, 1,4-dioxane, diethyl ether, tetrahydrothiophene,
and 1,3-dithiolane
Cross-Dehydrogenative Coupling of Azoles with α‑C(sp<sup>3</sup>)–H of Ethers and Thioethers under Metal-Free Conditions: Functionalization of H–N Azoles via C–H Activation
A metal-free cross-dehydrogenative
coupling method for the synthesis
of <i>N</i>-substituted azoles has been developed. The TBAI/TBHP
system catalyzed the coupling of azoles with ethers and thioethers
via α-CÂ(sp<sup>3</sup>)–H activation. Under the optimized
conditions, a diverse range of un/substituted azoles such as 1<i>H</i>-benzimidazole, 9<i>H</i>-purine, 1<i>H</i>-benzotriazole, 1<i>H</i>-1,2,3-triazole, 1<i>H</i>-1,2,4-triazole, and 1<i>H</i>-pyrazole were successfully
employed for coupling with various ethers and thioethers such as tetrahydrofuran,
tetrahydropyran, 1,4-dioxane, diethyl ether, tetrahydrothiophene,
and 1,3-dithiolane
Design of Novel 3‑Pyrimidinylazaindole CDK2/9 Inhibitors with Potent In Vitro and In Vivo Antitumor Efficacy in a Triple-Negative Breast Cancer Model
In
the present study, a novel series of 3-pyrimidinylazaindoles
were designed and synthesized using a bioinformatics strategy as cyclin-dependent
kinases CDK2 and CDK9 inhibitors, which play critical roles in the
cell cycle control and regulation of cell transcription. The present
approach gives new dimensions to the existing SAR and opens a new
opportunity for the lead optimizations from comparatively inexpensive
starting materials. The study led to the identification of the alternative
lead candidate <b>4ab</b> with a nanomolar potency against CDK2
and CDK9 and potent antiproliferative activities against a panel of
tested tumor cell lines along with a better safety ratio of ∼33
in comparison to reported leads. In addition, the identified lead <b>4ab</b> demonstrated a good solubility and an acceptable in vivo
PK profile. The identified lead <b>4ab</b> showed an in vivo
efficacy in mouse triple-negative breast cancer (TNBC) syngeneic models
with a TGI (tumor growth inhibition) of 90% without any mortality
growth inhibition in comparison to reported leads