ChemMedChem

Nature‐Inspired MYC Inhibitor Disrupts MYC‐Driven Glycolysis and Restricts Ovarian Tumor Growth

Myelocytomatosis oncogene (MYC) inhibitors are not available for clinical applications because the MYC protein is not part of a receptor‐ligand pair and lacks a defined binding site for small molecules. GD‐07, drug‐like small molecule identified throughcheminformatics that selectively binds to the G‐quadruplex (G4) in the c‐MYC promoter with high binding affinity and selectivity over dsDNA. NMR analysis reveals that GD‐07 binds to the upper tetrad of c‐MYC G4. It exhibits a favorable pharmacokinetic profile and high cytotoxicity in ovarian cancer (OC) cells (A2780) compared to the standard drug carboplatin. Normal cells show no sensitivity to GD‐07, indicating a broad therapeutic window. GD‐07 suppresses MYC expression, curbing glucose metabolism, and glycolysis while promoting p53 and proapoptotic markers in OC cells. In patient‐derived OC organoids, GD‐07 shows greater activity than carboplatin with promising clinical translatability.

Mithplatins: Mithramycin SA‐Pt(II) Complex Conjugates for the Treatment of Platinum‐Resistant Ovarian Cancers

AbstractDNA coordinating platinum (Pt) containing compounds cisplatin and carboplatin have been used for the treatment of ovarian cancer therapy for four decades. However, recurrent Pt‐resistant cancers are a major cause of mortality. To combat Pt‐resistant ovarian cancers, we designed and synthesized a conjugate of an anticancer drug mithramycin with a reactive Pt(II) bearing moiety, which we termed mithplatin. The conjugates displayed both the Mg2+‐dependent noncovalent DNA binding characteristic of mithramycin and the covalent crosslinking to DNA of the Pt. The conjugate was three times as potent as cisplatin against ovarian cancer cells. The DNA lesions caused by the conjugate led to the generation of DNA double‐strand breaks, as also observed with cisplatin. Nevertheless, the conjugate was highly active against both Pt‐sensitive and Pt‐resistant ovarian cancer cells. This study paves the way to developing mithplatins to combat Pt‐resistant ovarian cancers.

Calcification‐Based Cancer Diagnosis and Therapy

AbstractIn nature, calcium deposition is a common biological process in mammals that shapes mechanical structures and creates the functions of bones and teeth, and causes calculi formation. Spontaneous tumor calcification and regional lymph node calcification in colorectal cancer, lung cancer, and glioblastoma have been proven to be benign prognostic factors in the clinic. In line with this concept, we introduce the idea and lead the compound development of artificially inducing bionic calcification around the surface of cancer cells. This process is shown to have excellent effects in the inhibition of growth and metastases of cervical, breast, and lung tumors, as well as superb performance in early‐stage diagnosis. Therefore, we predict that this concept may open the door for cancer targeting calcification therapy and diagnosis and provide an outlook for a new avenue in anticancer drug development.

Discovery of Novel Fluorescent Azaindoles with Cytotoxic Action in A2780 Ovarian Carcinoma Cells

AbstractAzaindole scaffold is a privileged structure in medicinal chemistry and some derivatives have demonstrated to be potential anticancer drugs. Herein, a set of novel azaindoles, comprising the four regioisomers, bearing a morpholine (azaindoles 3 a‐d) and N‐methyl‐N‐benzylamine (azaindoles 4 a‐d) groups were prepared. Among these compounds, azaindoles 4 exhibited higher cytotoxicity against the ovarian cancer cell line A2780 and normal dermal fibroblasts compared to azaindoles 3. Furthermore, azaindoles 4 b and 4 c promoted a delay in the cell cycle of the cancer cell line, inspiring an investigation into the intracellular localization of these derivatives.

Nitidine and Paclitaxel‐Coloaded Lipid–Chitosan Hybrid Nanoparticles Overcoming ABCB1‐Mediated Multidrug Resistance in Ovarian Cancer

Multiple drug resistance, which leads to tumor recurrence and contributes to high mortality rates in ovarian cancer, must be overcome for successful treatment. Within this study, the efficacy of lipid–chitosan hybrid nanoparticles (LPHNPs) with NTD as an ABCB1 inhibitor and PTX as a chemotherapeutic agent in ABCB1 overexpressed ovarian cancer cells are explored. Sensitive ovarian cancer cells acquire resistance by continuous paclitaxel treatment and confirm by the resistance index and ABCB1 expression by quantitative reverse transcription polymerase chain reaction. PTX‐NTD‐loaded LPHNPs (N‐PTX‐LPHNPs) are synthesized via ionic gelation and characterized by the dynamic light scattering method, in vitro release, encapsulation, and loading efficiency, FTIR, and scanning electron microscopy. XTT, Rho‐123 accumulation assay, and DCFH‐DA staining are conducted to examine the drug resistance inhibition and anticancer activity of NTD and N‐PTX‐LPHNPs. Bioinformatics analyses are performed to evaluate the absorption, distribution, metabolism and excretion, toxicity properties of NTD and the interaction between the PTX‐NTD combination and ABCB1. NTD shows high binding affinity to ABCB1 and cytotoxicity against ovarian cancer cells. Moreover, the PTX‐NTD combination‐loaded nanoparticles increase PTX accumulation and intracellular ROS levels, enhance anticancer activity, and overcome resistance to ovarian cancer. The results highlight the NTD‐PTX‐loaded LPHNPs as a potential therapeutic for ABCB1 overexpressed ovarian cancer.

Small Molecule Antagonists of the DNA Repair ERCC1/XPA Protein‐Protein Interaction

AbstractThe DNA excision repair protein ERCC1 and the DNA damage sensor protein, XPA are highly overexpressed in patient samples of cisplatin‐resistant solid tumors including lung, bladder, ovarian, and testicular cancer. The repair of cisplatin‐DNA crosslinks is dependent upon nucleotide excision repair (NER) that is modulated by protein‐protein binding interactions of ERCC1, the endonuclease, XPF, and XPA. Thus, inhibition of their function is a potential therapeutic strategy for the selective sensitization of tumors to DNA‐damaging platinum‐based cancer therapy. Here, we report on new small‐molecule antagonists of the ERCC1/XPA protein‐protein interaction (PPI) discovered using a high‐throughput competitive fluorescence polarization binding assay. We discovered a unique structural class of thiopyridine‐3‐carbonitrile PPI antagonists that block a truncated XPA polypeptide from binding to ERCC1. Preliminary hit‐to‐lead studies from compound 1 reveal structure‐activity relationships (SAR) and identify lead compound 27 o with an EC50 of 4.7 μM. Furthermore, chemical shift perturbation mapping by NMR confirms that 1 binds within the same site as the truncated XPA67–80 peptide. These novel ERCC1 antagonists are useful chemical biology tools for investigating DNA damage repair pathways and provide a good starting point for medicinal chemistry optimization as therapeutics for sensitizing tumors to DNA damaging agents and overcoming resistance to platinum‐based chemotherapy.

Evaluation of a Radioiodinated G‐Quadruplex Binder in Cervical Cancer Models

AbstractWe herein describe the radiosynthesis of a 125I‐labeled acridine orange derivative ([125I]‐C8), acting as a G‐quadruplex binder, and its biological evaluation in cervical cancer models, aiming to enlighten its potential as a radioligand for Auger Electron Radiopharmaceutical Therapy (AE‐RPT) of cancer. [125I]‐C8 was synthesized with a moderate radiochemical yield (ca. 60 %) by a [125I]iodo‐destannylation reaction. Its evaluation in cervical cancer HeLa cells demonstrated that the radiocompound has a significant cellular internalization with a notorious accumulation in the cell nucleus. In line with these results, [125I]‐C8 strongly compromised the viability of HeLa cells in a dose‐dependent manner, inducing non‐repairable DNA lesions that are most probably due to the AEs emitted by 125I in close proximity to the DNA molecule. Biodistribution studies in a murine HeLa xenograft model showed that [125I]‐C8 has fast blood clearance and high in vivo stability but poor tumor uptake, after systemic administration. The respective supramolecular conjugate with the AS1411 aptamer ([125I]‐C8/AS1411) led to a slower blood clearance in the same animal tumor model, although without improving the tumor uptake. To take advantage of the radiotoxicity of [125I]‐C8 against cervical cancer cells other strategies need to be studied, based namely on alternative nanodelivery carriers and/or intratumoral injection approaches.

Screening Methods for Cervical Cancer

AbstractCervical cancer seriously affects the health of women worldwide. Persistent infection of high‐risk HPV (Human Papilloma Virus) can lead to cervical cancer. There is a great need for timely and efficient screening methods for cervical cancer. The current screening methods for cervical cancer are mainly based on cervical cytology and HPV testing. Cervical cytology is made of Pap smear and liquid‐based cytology, while HPV testing is based on immunological and nucleic acid level detection methods. This review introduces cervical cancer screening methods based on cytology and human papillomavirus testing in detail. The advantages and limitations of the screening methods are also summarized and compared.

Biodegradable Periodic Mesoporous Organosilica (BPMO) Loaded with Daunorubicin: A Promising Nanoparticle‐Based Anticancer Drug

AbstractBiodegradable periodic mesoporous organosilica (BPMO) nanoparticles have emerged as a promising type of nanocarrier for drug delivery, given the biodegradable feature is advantageous for clinical translation. In this paper, we report synthesis and characterization of daunorubicin (DNR) loaded BPMO. DNR was loaded onto rhodamine B‐labeled BPMO that contain tetrasulfide bonds. Tumor spheroids and chicken egg tumor models were used to characterize the activity in biological settings. In the first experiment we examined the uptake of BPMO into tumor spheroids prepared from ovarian cancer cells. BPMO were efficiently taken up into tumor spheroids and inhibited their growth. In the chicken egg tumor model, intravenous injection of DNR‐loaded BPMO led to the elimination of ovarian tumor. Lack of adverse effect on organs such as lung appears to be due to excellent tumor accumulation of BPMO. Thus, DNR‐loaded BPMO represents a promising nanodrug compared with free DNR currently used in cancer therapy. OK

New Platinum(II) Complexes Affecting Different Biomolecular Targets in Resistant Ovarian Carcinoma Cells

AbstractResistance to platinum‐based anticancer drugs represents an important limit for their clinical effectiveness and one of the most important field of investigation in the context of platinum compounds. From our previous studies, PtII complexes containing the triphenylphosphino moiety have been emerging as promising agents, showing significant cytotoxicity to resistant ovarian carcinoma cells. Two brominated triphenylphosphino trans‐platinum derivatives were prepared and evaluated on human tumor cell lines, sensitive and resistant to cisplatin. The new complexes exert a notable antiproliferative effect on resistant ovarian carcinoma cells, showing a remarkable intracellular accumulation and the ability to interact with different intracellular targets. The interaction with DNA, the collapse of mitochondrial transmembrane potential, and the impairment of intracellular redox state were demonstrated. Moreover, a selectivity towards the selenocysteine of thioredoxin reductase was observed. The mechanism of action is discussed with regard to the resistance phenomenon in ovarian carcinoma cells.

Copper(I)‐Thiosemicarbazone Complexes with Dual Anticancer and Antiparasitic Activity

AbstractFour new Cu(I) complexes of the general formula [Cu(PP)(LL)][BF4], in which PP is a phosphane ligand (triphenylphosphane or 1,2‐bis(diphenylphosphano)ethane (dppe)) and LL is a bioactive thiosemicarbazone ligand (4‐(methyl)‐1‐(5‐nitrofurfurylidene)thiosemicarbazone) or 4‐(ethyl)‐1‐(5‐nitrofurfurylidene)thiosemicarbazone) were synthesized and fully characterized by classical analytical and spectroscopic methods. The anti‐trypanosome and anticancer activities were investigated in vitro on Trypanosoma cruzi and in two human cancer cell lines (ovarian OVCAR3 and prostate PC3). To test the selectivity toward parasites and cancer cells, the cytotoxicity on normal monkey kidney VERO and human dermal fibroblasts HDF cells was also evaluated. The new heteroleptic complexes were more cytotoxic on T. cruzi and chemoresistant prostate PC3 cells than the benchmark drugs nifurtimox and cisplatin. The compounds also showed a high level of cellular internalization by the OVCAR3 cells and, in particular, those containing the dppe phosphane showed activation of the cell death mechanism via apoptosis. On the other hand, the production of reactive oxygen species induced by these complexes was not evident.