A comprehensive review on phosphatidylinositol-3-kinase (PI3K) and its inhibitors bearing pyrazole or indazole core for cancer therapy.

Cancer is a complex and multifaceted group of diseases with a high mortality rate characterized by uncontrolled proliferation of abnormal cells. Dysregulation of normal signalling pathways in cancer contributes to the different hallmarks of this disease. The signalling pathway of which phosphatidylinositol 3-kinase (PI3K) is a part is not an exception. In fact, dysregulated activation of PI3K signalling pathways can result in unbridled cellular proliferation and enhanced cell survival, thereby fostering the onset and advancement of cancer. Therefore, there is substantial interest in developing targeted therapies specifically aimed at inhibiting the PI3K enzyme and its associated pathways. Also, the therapeutic interest on pyrazoles and indazoles has been growing due to their various medicinal properties, namely, anticancer activity. Derivatives of these compounds have been studied as PI3K inhibitors, and they showed promising results. There are already some PI3K inhibitors approved by Food and Drug Administration (FDA), such as Idelalisib (Zydelig®) and Alpelisib (Piqray®). In this context, this review aims to address the importance of PI3K in cellular processes and its role in cancer. Additionally, it aims to report a comprehensive literature review of PI3K inhibitors, containing the pyrazole and indazole scaffolds, published in the last fifteen years, focusing on structure-activity relationship aspects, thus providing important insights for the design of novel and more effective PI3K inhibitors.

A review of poly(ADP-ribose)polymerase-1 (PARP1) role and its inhibitors bearing pyrazole or indazole core for cancer therapy.

Cancer is a disease with a high mortality rate characterized by uncontrolled proliferation of abnormal cells. The hallmarks of cancer evidence the acquired cells characteristics that promote the growth of malignant tumours, including genomic instability and mutations, the ability to evade cellular death and the capacity of sustaining proliferative signalization. Poly(ADP-ribose) polymerase-1 (PARP1) is a protein that plays key roles in cellular regulation, namely in DNA damage repair and cell survival. The inhibition of PARP1 promotes cellular death in cells with homologous recombination deficiency, and therefore, the interest in PARP protein has been rising as a target for anticancer therapies. There are already some PARP1 inhibitors approved by Food and Drug Administration (FDA), such as Olaparib and Niraparib. The last compound presents in its structure an indazole core. In fact, pyrazoles and indazoles have been raising interest due to their various medicinal properties, namely, anticancer activity. Derivatives of these compounds have been studied as inhibitors of PARP1 and presented promising results. Therefore, this review aims to address the importance of PARP1 in cell regulation and its role in cancer. Moreover, it intends to report a comprehensive literature review of PARP1 inhibitors, containing the pyrazole and indazole scaffolds, published in the last fifteen years, focusing on structure-activity relationship aspects, thus providing important insights for the design of novel and more effective PARP1 inhibitors.

Dicoumarol: from chemistry to antitumor benefits.

Dicoumarol, a coumarin-like compound, is known for its anticoagulant properties associated with the ability to inhibit vitamin K, being prescribed as a drug for several decades. The pharmaceutical value of dicoumarol turned it into a focus of chemists' attention, aiming its synthesis and of dicoumarol derivatives, bringing to light new methodologies. In recent years, several other bioactive effects have been claimed for dicoumarol and its derivatives, including anti-inflammatory, antimicrobial, antifungal, and anticancer, although the mechanisms of action underlying them are mostly not disclosed and additional research is needed to unravel them. This review presents a state of the art on the chemistry of dicoumarols, and their potential anticancer characteristics, highlighting the mechanisms of action elucidated so far. In parallel, we draw attention to the lack of in vivo studies and clinical trials to assess the safety and efficacy as drugs for later application.

Hypoxia-targeted cupric-tirapazamine liposomes potentiate radiotherapy in prostate cancer spheroids.

In this study, novel cupric-tirapazamine [Cu(TPZ)2]-liposomes were developed as an effective hypoxia-targeted therapeutic, which potentiated radiotherapy in a three dimensional (3D) prostate cancer (PCa) model. To overcome the low water solubility of the Cu(TPZ)2, a remote loading method was developed to efficiently load the lipophilic complex into different liposomal formulations. The effect of pH, temperature, PEGylation, lipid composition, liposome size, lipid: complex ratio on the liposome properties, and drug loading was evaluated. The highest loading efficiency was obtained at neutral pH, which was independent of lipid composition and incubation time. In addition, enhanced drug loading was achieved upon decreasing the lipid:complex molar ratio with minimal effects on liposomes' morphology. Interestingly, the in vitro potency of the developed liposomes was easily manipulated by changing the lipid composition. The hydrophilic nature of our liposomal formulations improved the complex's solubility, leading to enhanced cellular uptake and toxicity, both in PCa monolayers and tumour spheroids. Moreover, Cu(TPZ)2-loaded liposomes combined with radiation, showed a significant reduction in PCa spheroids growth rate, compared to the free complex or radiation alone, which could potentiate radiotherapy in patients with localised advanced PCa.

Therapeutic Potential of Glycosyl Flavonoids as Anti-Coronaviral Agents.

The COVID-19 pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has spread all over the world, creating a devastating socio-economic impact. Even though protective vaccines are starting to be administered, an effective antiviral agent for the prevention and treatment of COVID-19 is not available yet. Moreover, since new and deadly CoVs can emerge at any time with the potential of becoming pandemics, the development of therapeutic agents against potentially deadly CoVs is a research area of much current interest. In the search for anti-coronaviral drugs, researchers soon turned their heads towards glycosylated flavonoids. Glycosyl flavonoids, widespread in the plant kingdom, have received a lot of attention due to their widely recognized antioxidant, anti-inflammatory, neuroprotective, anticarcinogenic, antidiabetic, antimicrobial, and antiviral properties together with their capacity to modulate key cellular functions. The wide range of biological activities displayed by glycosyl flavonoids, along with their low toxicity, make them ideal candidates for drug development. In this review, we examine and discuss the up-to-date developments on glycosyl flavonoids as evidence-based natural sources of antivirals against coronaviruses and their potential role in the management of COVID-19.

Chloroxine overrides DNA damage tolerance to restore platinum sensitivity in high-grade serous ovarian cancer.

High-grade serous cancer (HGSC) accounts for ~67% of all ovarian cancer deaths. Although initially sensitive to platinum chemotherapy, resistance is inevitable and there is an unmet clinical need for novel therapies that can circumvent this event. We performed a drug screen with 1177 FDA-approved drugs and identified the hydroxyquinoline drug, chloroxine. In extensive validation experiments, chloroxine restored sensitivity to both cisplatin and carboplatin, demonstrating broad synergy in our range of experimental models of platinum-resistant HGSC. Synergy was independent of chloroxine's predicted ionophore activity and did not relate to platinum uptake as measured by atomic absorption spectroscopy. Further mechanistic investigation revealed that chloroxine overrides DNA damage tolerance in platinum-resistant HGSC. Co-treatment with carboplatin and chloroxine (but not either drug alone) caused an increase in γH2AX expression, followed by a reduction in platinum-induced RAD51 foci. Moreover, this unrepaired DNA damage was associated with p53 stabilisation, cell cycle re-entry and triggering of caspase 3/7-mediated cell death. Finally, in our platinum-resistant, intraperitoneal in vivo model, treatment with carboplatin alone resulted in a transient tumour response followed by tumour regrowth. In contrast, treatment with chloroxine and carboplatin combined, was able to maintain tumour volume at baseline for over 4 months. In conclusion, our novel results show that chloroxine facilitates platinum-induced DNA damage to restore platinum sensitivity in HGSC. Since chloroxine is already licensed, this exciting combination therapy could now be rapidly translated for patient benefit.

Enhanced selectivity, cellular uptake, and in vitro activity of an intrinsically fluorescent copper-tirapazamine nanocomplex for hypoxia targeted therapy in prostate cancer.

In the present work, a copper-tirapazamine (TPZ) nanocomplex [Cu(TPZ)2] was synthesized for selective hypoxia-targeted therapy. The nanocomplex revealed a crystalline form, and exhibited higher lipophilicity, compared to TPZ. Furthermore, its stability was confirmed in different media, with minimum dissociation in serum (∼20% up to 72 h). In contrast to other hypoxia-targeted agents, our intrinsically fluorescent nanocomplex offered an invaluable tool to monitor its cellular uptake and intracellular distribution under both normoxia and hypoxia. The conferred higher cellular uptake of the nanocomplex, especially under hypoxia, and its biocompatible reductive potential resulted in superior hypoxia selectivity in two prostate cancer (PC) cell lines. More promisingly, the nanocomplex showed higher potency in three-dimensional tumor spheroids, compared to TPZ, due to its slower metabolism, and probably deeper penetration in tumor spheroids. Interestingly, the nuclear localization of the intact nanocomplex, combined with its higher DNA binding affinity, as evidenced by the DNA binding assay, resulted in significant S-phase cell-cycle arrest, followed by apoptosis in the three-dimensional spheroid model. In conclusion, the presented findings suggested that the Cu(TPZ)2 nanocomplex can be a promising hypoxia-targeted therapeutic, which could potentiate the efficacy of the existing chemo- and radiotherapy in PC.

Natural and Biomimetic Antitumor Pyrazoles, A Perspective.

The present review presents an overview of antitumor pyrazoles of natural or bioinspired origins. Pyrazole compounds are relatively rare in nature, the first ones having been reported in 1966 and being essentially used as somniferous drugs. Cytotoxic pyrazoles of natural sources were first isolated in 1969, and a few others have been reported since then, most of them in the last decade. This paper presents a perspective on the current knowledge on antitumor natural pyrazoles, organized into two sections. The first focuses on the three known families of cytotoxic pyrazoles that were directly isolated from plants, for which the knowledge of the medicinal properties is in its infancy. The second section describes pyrazole derivatives of natural products, discussing their structure-activity relationships.

Synthesis of Chromone-Related Pyrazole Compounds.

Chromones, six-membered oxygen heterocycles, and pyrazoles, five-membered two-adjacent-nitrogen-containing heterocycles, represent two important classes of biologically active compounds. Certain derivatives of these scaffolds play an important role in medicinal chemistry and have been extensively used as versatile building blocks in organic synthesis. In this context, we will discuss the most relevant advances on the chemistry that involves both chromone and pyrazole rings. The methods reviewed include the synthesis of chromone-pyrazole dyads, synthesis of chromone-pyrazole-fused compounds, and chromones as starting materials in the synthesis of 3(5)-(2-hydroxyaryl)pyrazoles, among others. This review will cover the literature on the chromone and pyrazole dual chemistry and their outcomes in the 21st century.

Exploiting the cancer niche: Tumor-associated macrophages and hypoxia as promising synergistic targets for nano-based therapy.

The tumor microenvironment has been widely exploited as an active participant in tumor progression. Extensive reports have defined the dual role of tumor-associated macrophages (TAMs) in tumor development. The protumoral effect exerted by the M2 phenotype has been correlated with a negative outcome in most solid tumors. The high infiltration of immune cells in the hypoxic cores of advanced solid tumors leads to a chain reaction of stimuli that enhances the expression of protumoral genes, thrives tumor malignancy, and leads to the emergence of drug resistance. Many studies have shown therapeutic targeting systems, solely to TAMs or tumor hypoxia, however, novel therapeutics that target both features are still warranted. In the present review, we discuss the role of hypoxia in tumor development and the clinical outcome of hypoxia-targeted therapeutics, such as hypoxia-inducible factor (HIF-1) inhibitors and hypoxia-activated prodrugs. Furthermore, we review the state-of-the-art of macrophage-based cancer therapy. We thoroughly discuss the development of novel therapeutics that simultaneously target TAMs and tumor hypoxia. Nano-based systems have been highlighted as interesting strategies for dual modality treatments, with somewhat improved tissue extravasation. Such approach could be seen as a promising strategy to overcome drug resistance and enhance the efficacy of chemotherapy in advanced solid and metastatic tumors, especially when exploiting cell-based nanotherapies. Finally, we provide an in-depth opinion on the importance of exploiting the tumor microenvironment in cancer therapy, and how this could be translated to clinical practice.

Selection of Novel Peptides Homing the 4T1 CELL Line: Exploring Alternative Targets for Triple Negative Breast Cancer.

The use of bacteriophages to select novel ligands has been widely explored for cancer therapy. Their application is most warranted in cancer subtypes lacking knowledge on how to target the cancer cells in question, such as the triple negative breast cancer, eventually leading to the development of alternative nanomedicines for cancer therapeutics. Therefore, the following study aimed to select and characterize novel peptides for a triple negative breast cancer murine mammary carcinoma cell line- 4T1. Using phage display, 7 and 12 amino acid random peptide libraries were screened against the 4T1 cell line. A total of four rounds, plus a counter-selection round using the 3T3 murine fibroblast cell line, was performed. The enriched selective peptides were characterized and their binding capacity towards 4T1 tissue samples was confirmed by immunofluorescence and flow cytometry analysis. The selected peptides (4T1pep1 -CPTASNTSC and 4T1pep2-EVQSSKFPAHVS) were enriched over few rounds of selection and exhibited specific binding to the 4T1 cell line. Interestingly, affinity to the human MDA-MB-231 cell line was also observed for both peptides, promoting the translational application of these novel ligands between species. Additionally, bioinformatics analysis suggested that both peptides target human Mucin-16. This protein has been implicated in different types of cancer, as it is involved in many important cellular functions. This study strongly supports the need of finding alternative targeting systems for TNBC and the peptides herein selected exhibit promising future application as novel homing peptides for breast cancer therapy.

Synthesis, antibacterial and cytotoxic activities of new biflorin-based hydrazones and oximes.

Biflorin 1 is a biologically active quinone, isolated from Capraria biflora. Five new biflorin-based nitrogen derivatives were synthesized, of which two were mixtures of (E)- and (Z)- isomers: (Z)-2a, (Z)-2b, (Z)-3a, (Z)- and (E)-3b, (Z)- and (E)-3c. The antibacterial activity was investigated using the microdilution method for determining the minimum inhibitory concentration (MIC) against six bacterial strains. Tests have shown that these derivatives have potential against all bacterial strains. The cytotoxic activity was also evaluated against three strains of cancer cells, but none of the derivatives showed activity.