Anti-Cancer Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry - Anti-Cancer Agents) - Volume 20, Issue 11, 2020

Background: Silver nanoparticles (AgNPs) are well-known as a promising antimicrobial material; they have been widely used in many commercial products against pathogenic agents. Despite a growing concern regarding the cytotoxicity, AgNPs still have attracted considerable interest worldwide to develop a new generation of diagnostic tool and effective treatment solution for cancer cells. Objective: This paper aims to review the advances of AgNPs applied for cancer diagnosis and treatment. Methods: The database has been collected, screened and analysed through up-to-date scientific articles published from 2007 to May 2019 in peer-reviewed international journals. Results: The findings of the database have been analysed and divided into three parts of the text that deal with AgNPs in cancer diagnosis, their cytotoxicity, and the role as carrier systems for cancer treatment. Thanks to their optical properties, high conductivity and small size, AgNPs have been demonstrated to play an essential role in enhancing signals and sensitivity in various biosensing platforms. Furthermore, AgNPs also can be used directly or developed as a drug delivery system for cancer treatment. Conclusion: The review paper will help readers understand more clearly and systematically the role and advances of AgNPs in cancer diagnosis and treatment.

The panorama of cancer treatment has taken a considerable leap over the last decade with the advancement in the upcoming novel therapies combined with modern diagnostics. Nanotheranostics is an emerging science that holds tremendous potential as a contrivance by integrating therapy and imaging in a single probe for cancer diagnosis and treatment thus offering the advantage like tumor-specific drug delivery and at the same time reduced side effects to normal tissues. The recent surge in nanomedicine research has also paved the way for multimodal theranostic nanoprobe towards personalized therapy through interaction with a specific biological system. This review presents an overview of the nano theranostics approach in cancer management and a series of different nanomaterials used in theranostics and the possible challenges with future directions.

Breast cancer is the second most common cancer that causes death among women worldwide. Incidence of breast cancer is increasing worldwide, and the age at which breast cancer develops has shifted from 50- 70 years to 30-40 years. Chemotherapy is the most commonly used effective treatment strategy to combat breast cancer. However, one of the major drawbacks is low selective site-specificity and the consequent toxic insult to normal healthy cells. The nanocarrier system is consistently utilised to minimise the various limitations involved in the conventional treatment of breast cancer. The nanocarrier based targeted drug delivery system provides better bioavailability, prolonged circulation with an effective accumulation of drugs at the tumour site either by active or passive drug targeting. Active targeting has been achieved by receptor/protein anchoring and externally guided magnetic nanocarriers, whereas passive targeting accomplished by employing the access to the tunnel via leaky tumour vasculature, utilising the tumour microenvironment, because the nanocarrier systems can reduce the toxicity to normal cells. As of now a few nanocarrier systems have been approved by FDA, and various nanoformulations are in the pipeline at the preclinical and clinical development for targeting breast cancer; among them, polymeric micelles, microemulsions, magnetic microemulsions, liposomes, dendrimers, carbon nanotubes, and magnetic Nanoparticles (NPs) are the most common. The current review highlights the active and passive targeting potential of nanocarriers in breast cancer and discusses their role in targeting breast cancer without affecting normal healthy cells.

Replication fork reversal and restart has gained immense interest as a central response mechanism to replication stress following DNA damage. Although the exact mechanism of fork reversal has not been elucidated precisely, the involvement of diverse pathways and different factors has been demonstrated, which are central to this phenomenon. RecQ helicases known for their vital role in DNA repair and maintaining genome stability has recently been implicated in the restart of regressed replication forks. Through interaction with vital proteins like Poly (ADP) ribose polymerase 1 (PARP1), these helicases participate in the replication fork reversal and restart phenomenon. Most therapeutic agents used for cancer chemotherapy act by causing DNA damage in replicating cells and subsequent cell death. These DNA damages can be repaired by mechanisms involving fork reversal as the key phenomenon eventually reducing the efficacy of the therapeutic agent. Hence the factors contributing to this repair process can be good selective targets for developing more efficient chemotherapeutic agents. In this review, we have discussed in detail the role of various proteins in replication fork reversal and restart with special emphasis on RecQ helicases. Involvement of other proteins like PARP1, recombinase rad51, SWI/SNF complex has also been discussed. Since RecQ helicases play a central role in the DNA damage response following chemotherapeutic treatment, we propose that targeting these helicases can emerge as an alternative to available intervention strategies. We have also summarized the current research status of available RecQ inhibitors and siRNA based therapeutic approaches that targets RecQ helicases. In summary, our review gives an overview of the DNA damage responses involving replication fork reversal and provides new directions for the development of more efficient and sustainable chemotherapeutic approaches.

Background and Objective: Cyclodextrins have been of great interest as excellent candidates for fabricating versatile nano-drug delivery systems due to their commercial availability, easy functionalization, low immunogenicity, biocompatibility and safety. The possibility of reversible inclusion complex formation between cyclodextrins and various guest molecules in association with versatile exclusive properties of cyclodextrins offer a route towards the fabrication of highly sophisticated nanostructures with enormous potential for cancer treatment. Methods and Results: The current review discusses important recent advances in the fabrication and development of cyclodextrin-based nanostructures for cancer therapy. Firstly, the formation of inclusion complexes between cyclodextrin derivatives and anticancer compounds, as well as their application, are summarized. Secondly, the cyclodextrins -based nanosystems including cyclodextrin-containing polymers, cyclodextrin-based supramolecular necklaces, which consist of polyrotaxanes and polypseudorotaxanes and cyclodextrin based hydrogels accompanied by their applications in cancer treatment are highlighted. In the end, the future perspective of this field is discussed. Conclusion: Numerous investigations in this area pave the way for the flourishing of the next generation of nano-therapeutics towards enhanced cancer therapy.

Background and Objective: Graphene-based nanomaterials have received increasing attention due to their unique physical-chemical properties including two-dimensional planar structure, large surface area, chemical and mechanical stability, superconductivity and good biocompatibility. On the other hand, graphene-based nanomaterials have been explored as theranostics agents, the combination of therapeutics and diagnostics. In recent years, grafting hydrophilic polymer moieties have been introduced as an efficient approach to improve the properties of graphene-based nanomaterials and obtain new nanoassemblies for cancer therapy. Methods and Results: This review would illustrate biodistribution, cellular uptake and toxicity of polymergraphene nanoassemblies and summarize part of successes achieved in cancer treatment using such nanoassemblies. Conclusion: The observations showed successful targeting functionality of the polymer-GO conjugations and demonstrated a reduction of the side effects of anti-cancer drugs for normal tissues.

Background: Breast cancer is the most relevant type of cancer and the second cause of cancer- related deaths among women in general. Currently, there is no effective treatment for breast cancer although advances in its initial diagnosis and treatment are available. Therefore, the value of novel anti-tumor therapeutic modalities remains an immediate unmet need in clinical practice. Following our previous work regarding the properties of the Pluronics with different photosensitizers (PS) for photodynamic therapy (PDT), in this study we aimed to evaluate the efficacy of supersaturated hypericin (HYP) encapsulated on Pluronic® P123 (HYP/P123) against breast cancer cells (MCF-7) and non-tumorigenic breast cells (MCF-10A). Methods: Cell internalization and subcellular distribution of HYP/P123 was confirmed by fluorescence microscopy. The phototoxicity and citototoxicity of HYP/P123 was assessed by trypan blue exclusion assay in the presence and absence of light. Long-term cytotoxicity was performed by clonogenic assay. Cell migration was determined by the wound-healing assay. Apoptosis and necrosis assays were performed by annexin VFITC/ propidium Iodide (PI) by fluorescence microscopy. Results: Our results showed that HYP/P123 micelles had high stability and high rates of binding to cells, which resulted in the selective internalization in MCF-7, indicating their potential to permeate the membrane of these cells. Moreover, HYP/P123 micelles accumulated in mitochondria and endoplasmic reticulum organelles, resulting in the photodynamic cell death by necrosis. Additionally, HYP/P123 micelles showed effective and selective time- and dose dependent phototoxic effects on MCF-7 cells but little damage to MCF-10A cells. HYP/P123 micelles inhibited the generation of cellular colonies, indicating a possible capability to prevent the recurrence of breast cancer. We also demonstrated that HYP/P123 micelles inhibit the migration of tumor cells, possibly by decreasing their ability to form metastases. Conclusion: Taken together, the results presented here indicate a potentially useful role of HYP/P123 micelles as a platform for HYP delivery to more specifically and effectively treat human breast cancers through photodynamic therapy, suggesting they are worthy for in vivo preclinical evaluations.

Background: Isoindole-1,3(2H)-dione derivatives are known to have cytotoxic effects on many cancer cells. The anticancer activity of these compounds varies depending on the substituents attached to them. Therefore, the effect of substituents is very important when determining the anticancer activities of molecules. We have recently reported an example of the substituent effect. According to that work, the anticancer activity against HeLa, C6, and A549 cancer cell lines of isoindole- 1,3(2H)-dione compounds containing tert-butyldiphenylsilyl ether, azido, and hydroxyl groups was examined by our group. It was found that an isoindole-1,3(2H)-dione compound containing both tert-butyldiphenylsilyl ether group and azido groups showed higher anticancer activity than 5-fluorouracil and another isoindole-1,3(2H)- dione compound containing both azido and hydroxyl groups. After we discovered that tert-butyldiphenylsilyl ether group in the skeletal structure of isoindole-1,3(2H)-dione exhibits anticancer activity against HeLa, C6, and A549 cancer cell lines, we wanted to examine the anticancer activities of different silyl ether groups, i.e., OTMS, -OTBDPS, and -OTBDMS groups, and also -OH and -Br groups, by comparing them with each other according to the structure–activity relationship. Methods: All of the synthesized compounds were characterized by 1H and 13C NMR spectra, IR spectroscopy, and mass spectra measurements. The IC50 values of these compounds were calculated for all cancer cell lines and compared with each other and cisplatin, which is a platinum-containing chemotherapeutic drug. Molecular modelling studies were carried out using the MOE software package. Results: It was found that compounds 13 and 16, containing both silyl ether (-OTBDMS) and -Br groups, showed higher anticancer activity than cisplatin against both Caco-2 and MCF-7 cell lines. Compounds 20 and 23 showed anticancer activity in MCF-7 cells and compounds 8, 9, 20, and 23 in Caco-2 cells. While compounds 20 and 23 have only a silyl ether (-OTMS) group, compounds 8 and 9 have only a -OH group. Molecular modelling studies indicated that compounds 8 and 13, as well as their analogs, may bind to the active site of hRS6KB1 (pdb: 4l3j), compound 11 may bind to the active site of human mTOR (pdb: 4jt5) and additionally, compounds 10-17 are expected to be both mutagenic and reactive according to the mutagenicity and reactivity calculations. Conclusion: According to these results, the anticancer activities of isoindole-1,3(2H)-dione compounds (8 - 23) vary depending on the groups they contain and these groups affect each other's activities. Silyl ethers (-OTBDMS and -OTMS) and -OH and -Br groups in the skeletal structure of isoindole-1,3(2H)-dione can be regarded as anticancer agents. In this sense, compounds 13 and 16, containing both silyl ether (-OTBDMS) and - Br groups, may be regarded as alternative chemotherapeutic drugs. This work may lead to the synthesis of new isoindole-1,3(2H)-dione compounds containing different silyl ether groups and studies evaluating their anticancer activities or other biological properties.

Background: The 2-amino 1,3,4-thiadiazole framework has attracted considerable interest because of its prevalence in compounds possessing a wide range of pharmacological properties including anticancer/antitumor activities. Though a number of methods have been reported for the synthesis of this class of compounds, some of them are not straightforward, inexpensive and environmentally friendly. Objective: To synthesize 2-amino-1,3,4-thiadiazole derivatives that could act as potential anticancer agents. Methods: The use of lemon juice as an inexpensive and readily available biocatalyst was explored in the synthesis of 2-amino 1,3,4-thiadiazole derivatives. Accordingly, a convenient method has been developed for the rapid synthesis of this class of compounds under a mild and non-hazardous reaction condition in good yields. The methodology involved the reaction of various acid hydrazides with TMSNCS in the presence of lemon juice in PEG-400 at room temperature (25-30°C) under ultrasound irradiation. These compounds were assessed for their cytotoxic properties against two different metastatic breast cancer cell lines e.g., MDAMB-231 and MCF-7 and subsequently against SIRT1. Results: The 2-amino 1,3,4-thiadiazole derivatives 3a, 3i, 3j and 3l showed promising growth inhibition of MDAMB- 231 and MCF-7 cell lines and SIRT1 inhibition in vitro. Indeed, 3i was found to be a potent inhibitor of SIRT1. Conclusion: An ultrasound-assisted method facilitated by lemon juice has been developed to synthesize 2-amino- 1,3,4-thiadiazole derivatives that could act as potential anticancer agents.

Background: Quercetin is a flavonol from the flavonoid group of polyphenols, which positively affects human health due to its anti-cancer, anti-inflammatory, anti-microbial and cardioprotective effects. The effects of phenolic compounds, including quercetin, on programmed cell death and cellular senescence, have been the subject of research in recent years. Objective: In this study, we aimed to investigate the effects of quercetin on cell viability, apoptosis and cellular senescence in primary (Colo-320) and metastatic (Colo-741) colon adenocarcinoma cell lines. Methods: Cytotoxicity was analyzed via MTT assay in Colo-320 and Colo-741 cell lines. After quercetin treatment, cell ularsenescence and apoptosis were evaluated by TUNEL staining, X-Gal staining and indirect peroxidase technique for immunocytochemical analysis of related proteins such as Bax, Bcl-2, caspase-3, Hsp27, Lamin B1, p16, cyclin B1. Results: The effective dose for inhibition of cell growth in both cell lines was determined to be 25μg/ml quercetin for 48 hours. Increased Baximmunoreactivityfollowingquercetin treatment was significant in both Colo-320 and Colo-741 cell lines, but decreased Bcl-2 immunoreactivitywas significant only in theColo-320 primary cell line. In addition, after quercetin administration, the number of TUNEL positive cells and, immunoreactivities for p16, Lamin B1 and cyclin B1 in both Colo-320 and Colo-741 cells increased. Conclusion: Our results suggest that quercetin may only induce apoptosis in primary colon cancer cells. Furthermore, quercetin also triggered senescence in colon cancer cells, but some cells remained alive, suggesting that colon cancer cells might have escaped from senescence.