Anti-Cancer Agents in Medicinal Chemistry (v.17, #4)

Meet Our Editorial Board Member by Kyu Lim (471-471).

Cancer patients, though frequently entering complete remission after successful surgery, and/or irradiation, and chemotherapy years or even decades later may exhibit overt metastases and aggressive, mostly fatal recurrence on the basis of clinically silent persistence of disseminated tumor cells. Cellular dormancy is a mode of hibernation/ inactivity caused by a temporary mitotic arrest. It represents the critical phenomenon of latency making metastatic cancer cells highly refractory to conventional therapies. Regarding host-tumor interactions a broad range of dynamic, interrelated molecular events may influence the dormancy state of quiescence, like regulators of cell cycle arrest, stress signaling pathways, autophagy, microenvironmental, angiogenic and immunologic factors, genetic and epigenetic effects. Nonetheless, the underlying mechanisms are still poorly understood. Moreover, a distinct subset of circulating and disseminated cancer cells exhibits stem cell-like properties with direct tumor-provoking and metastatis-initiating capacity, being at least partly responsible for the specific dormancy features. In residual disease a future more detailed molecular and phenotypic characterization of disseminated tumor cells could represent the prerequisite not only for prognostic and staging purposes, but for a specific design of therapeutic targeting, as well. By understanding the elusive dormancy signatures of tumor cells, their cell- and context (microenvironment)-dependent modulation should provide novel potential therapeutic approaches to avoid or overcome metastatic cancer relapse.

NF-κB Signaling Pathway Inhibitors as Anticancer Drug Candidates by Maria Letícia de Castro Barbosa, Raissa Alves da Conceicao, Aline Guerra Manssour Fraga, Barbara Dias Camarinha, Gabriela Cristina de Carvalho Silva, Antonio Gilcler Ferreira Lima, Elisama Azevedo Cardoso, Viviane de Oliveira Freitas Lione (483-490).
Cancer incidence represents an important public health problem worldwide. Nuclear factor kappa B (NF- κB) transcription factor plays a pivotal role in the regulation of genes that control various responses in eukaryotic cells, including proliferation and survival, cytoskeletal remodeling, cellular adhesion and apoptosis. Extensive studies have demonstrated the contribution of NF-κB transcription in the promotion and progression of several hematological malignancies and solid tumors, in which NF-κB constitutive activation and/or overexpression are common clinical features. Moreover, triggering the NF-κB pathway is already considered one of the important mechanisms of resistance development to chemotherapy and radiotherapy, indicating that the inhibition of this signaling cascade is a promising approach to enhancing efficacy and preventing acquired resistance in cancer treatment. In this review, research efforts dedicated to the identification of novel NF-κB signaling pathway inhibitors as promising anticancer drug candidates are described.

Triple Negative Breast Cancer: A Tale of Two Decades by Arwa M. Ali, Jawaher A.K. Ansari, Nashwa M. Abd El-Aziz, Waleed N. Abozeed, Ahmed M. Abdel Warith, Khalid Alsaleh, Jean-Marc Nabholtz (491-499).
Triple negative breast cancer (TNBC) is a heterogeneous disease entity constituting about 15% of breast cancer cases worldwide. TNBC is associated with poor prognosis and lack of sustained response to conventional chemotherapeutic agents. Tumoral heterogeneity and the presence of several subtypes of TNBC such as Basal like (BL)-1, BL-2, immune-modulatory, luminal androgen receptor, mesenchymal, and mesenchymal/stem like subtype and claudin low subtype, may explain some of the difficulties faced in managing this challenging disease subgroups.

Although no approved targeted therapy is available for TNBCs, molecular-profiling efforts have revealed promising molecular targets such as the vascular endothelial growth factor (VEGF), epidermal growth factor receptor (EGFR), polyadenosine ribose polymerase inhibitors (PARPi) and DNA repair pathway, androgen pathway, and NOTCH pathway. TNBC is subject to intense research activities aiming at dissecting potential pathways, identifying potential molecular signatures and biomarkers in order to properly develop new targeted biologic modifiers. Despite this, there is a lack of approved predictive and prognostic biomarkers, and keeping in view the complexity of TNBC biology, research should be targeted towards identifying multi-factorial signatures rather than single markers. This review aims to summarize the current evidence, ongoing research and discuss future strategies for the treatment of patients with TNBC. In addition we have reviewed the recent advances in detecting predictive and prognostic biomarkers and identifying surrogate markers for early identification of potential responders to the new therapies.


The chemistry of heterocyclic containing, 1,3,4-thiadiazole has been an interesting field of study from ancient years. Subsequently, 1,3,4-thiadiazole nucleus constitutes a significant class of compounds for new drug development. Recently, various 1,3,4-thiadiazole derivatives synthesized and evaluated their biological activities including antimicrobial, antituberculosis, antioxidant, anti-inflammatory, anticonvulsants, antidepressant and anxiolytic, antihypertensive, anticancer and antifungal activity. The search for anticancer compounds with more selective activities and lower side effect continues to be an active area of argument examination in medicinal chemistry. This review elaborately described the medicinal chemistry, their structural activity relationship, and anticancer properties with respect to human cell line based approach related to synthesized 1,3,4-thiadiazole derivatives.

Background: Peroxisome proliferator-activated receptor gamma (PPARγ) is a nuclear receptor that regulates the expression of many genes relevant to carcinogenesis. By analogy to selective estrogen receptor modulator for treatment of cancer, selective or partial PPARγ agonists are considered clinically important for chemotherapy of cancer.

Objective: In this study we have rationally modified the structure of existing p-coumaric acid and ferulic acid, which would selectively activate PPARγ and exert their anti-proliferative effect at lower dose as compared to natural phytoconstituents.

Method: A series of p-coumaric (3a-3y) and ferulic acid (4a-4y) derivatives were designed as docked and virtually studied for their molecular properties using suitable software. Synthesized derivatives were assessed to check their effect on non-transformed hepatocytes using MTT assay. The final products, 3a-3y and 4a-4y, substituted 4- hydroxycinnamic acid derivatives and ferulic acid derivatives respectively were synthesized by stirring compound 1a or 1b with compounds 2a-2y (molar ratio- 1:2) for 24 hours, in presence of K2CO3, using dimethyl formamide (DMF) as the solvent. Synthesized molecules were characterized by 1HNMR, 13C NMR, Mass and elemental analysis. Synthesized molecules were studied for their antiproliferative activity by SRB assay. Compounds were screened further evaluated for PPARγ activating assay, cell cycle analysis (propidium iodide) and westernblot analysis.

Results: Molecules 3c, 3m, 4c and 4m were found to have GI50 value less than 50μM. These molecules were found to block G0/G1 phase of cell cycle in dose dependent manner. Western blot analysis revealed that these molecules inhibit proliferating cell nuclear antigen (PCNA) and cyclin D1 expression.

Conclusion: Collectively, these results suggest that these molecules could play a role as a novel therapeutic strategy for chronic myeloid leukemia.


Background: Cancer is one of the severest diseases in the world, and lung cancer is one of the five common cancers causing thousands of deaths every year. Moreover, most of the lung cancer patients die because of bone metastasis.

Methods: This research was conducted with the aim of developing novel nanoparticles (NPs) of docetaxel (DTX) loaded bovine serum albumin (BSA) conjugated docosahexaenoic acid (DHA) using an emulsion/solvent evaporation method for inhibiting lung cancer metastasis to bone. The in vitro drug release of the DTX-DHA-BSA-NPs showed that the nanoparticles released in a sustained and controlled manner contributed to continual fight against cancer cells. The study results revealed that the DTX-DHA-BSA-NPs had higher antitumor efficacy in comparison with the DTXBSA- NPs or DTX in vitro.

Result: The study results also showed that the DTX-DHA-BSA-NPs had higher inhibiting efficacy of lung cancer metastasis to bone in comparison with the DTX-BSA-NPs or DTX in vivo. Furthermore, the mean survival time was longer with DTX-DHA-BSA-NPs (24.40 d) than that of DTX (20.95 d). In consideration of these results, the DTXDHA- BSA-NPs may hold potential for bone metastasis of lung cancer treatment.


Background: Microtubules are dynamic filamentous cytoskeletal proteins which have used widely in cancer chemotherapy. Generally, the action of these compounds depends on binding to the tubulin proteins which are α, β -heterodimers that form the core of the microtubules. Arylthioindoles (ATIs) inhibit tubulin polymerization by binding to the colchicine site, inhibiting the binding of colchicine to tubulin. QSAR modeling play an important role in modern medicinal chemistry, presenting a unique potential for transforming the early phases of drug research, in terms of time and money savings. In this study we are intending to achieve some useful information about the structural properties of mentioned ATIs using the QSAR modeling method. In this research, the QSAR modeling has been employed to evaluate the efficacy of ATIs derivatives in the inhibition of tubulin polymerization. The best multivariate linear model for each training and test data subset calculated using both genetic algorithm-multiple linear regressions (GA-MLR) and stepwise-multiple linear regressions (S-MLR) methods. The best RS trial set has been selected by comparing the two different QSAR modeling results in all train and test subsets. Finally, the S-MLR and GA-MLR results were compared for finding the best random selection (RS) subset.

Methods: The molecular structures and experimental activity values for inhibition of tubulin polymerization obtained from the literature. Here, using Dragon package over 1185 molecular descriptors such as RDF, GETAWAY, WHIM, 3D-MoRSE descriptors, and functional group descriptors derived for proper characterizing the arylthioindole derivatives structures. These molecular descriptors reduced to 437 one by eliminating the constant variables, collinear descriptors and the variables having low correlation with response. In fact in order to obtain the best RS subsets in the mentioned method, the random samplings of the training subset (80% of data) were carried out 20 times and the remaining molecules (20% of data) considered as external validation set. The QSAR models were constructed using stepwise-MLR and GA-MLR.

Results: In order to select important variables the GA-MLR and S-MLR methods applied on the training subsets after data splitting. The best MLR models (models with high fitness function values) with four, five and six variables built to obtain the best QSAR model. The best MLR model had four parameters in both GA-MLR and S-MLR methods. The best significant relationships, using comparison of Q2 of models, for the IC50 values of tubulin assembly in the models obtained in S-MLR and GA-MLR methods are presented for all of the random sets and SOM set.

Conclusion: The result of external validation indicates that in the study of inhibition of tubulin polymerization, the Q2test values are 0.7242 and 0.3215 for GA-MLR and S-MLR methods respectively. Considering the results which obtained in both methods it can be concluded that in variable selecting the GA-MLR method is more powerful than the S-MLR method.


A 3D-QSAR Study on Betulinic Acid Derivatives as Anti-Tumor Agents and the Synthesis of Novel Derivatives for Modeling Validation by Weimin Ding, Sheng Zhang, Meixuan Zhu, Shaoming Wang, Tao Xu, Haijing Qu, Tao Yu, Xiufeng Yan, Yang Wang (566-575).
Background: Betulinic acid is a lupane-type triterpene firstly extracted from the bark of white birch. It has displayed anti-inflammatory, antioxidant, anti-HIV and selective cytotoxicity.

Objective: To understand the structure- anti-tumor activity relationship of betulinic acid and betulin derivatives and to synthesize novel anti-tumor derivatives of betulinic acid and betulin.

Method: The 3D-QSAR methods including CoMFA and CoMSIA methods were performed to study the structureanti- tumor activity relationship of betulinic acid (BA) and betulin (BE) derivatives.

Results: According to the models, near the C-3 site, non-bulky, negatively charged electron-donating, hydrophobic, non-hydrogen-bond-donating and hydrogen-bond-accepting groups are favored to the activity. Around the C-28 site, the bulky, positively charged electron-withdrawing and hydrophobic groups are favored, whereas hydrophilic groups may be introduced at the terminal of the side chain. Based on the models, BA and BE were esterified with substituted amino acid derivatives achieving novel derivatives for the modeling validation.

Conclusion: The experimental results verified the modeling rules, and showed when different rules may apply to the new structures, the steric effects might be more important. The synthesized derivatives were showed promising cytotoxicity against tested cancer cell lines.


4-Methylumbelliferones Analogues as Anticancer Agents: Synthesis and in Cell Pharmacological Studies by Ri-Zhen Huang, Shi-Xian Hua, Cai-Yi Wang, Ying-Ming Pan, Jian-Mei Qin, Zhan-Yu Ding, Ye Zhang, Heng-Shan Wang (576-589).
Background: Cancer is one of the most serious clinical problems worldwide, and considerable efforts have been devoted to discovering therapeutic agents with novel modes of action. Natural and synthetic coumarin derivatives have attracted intense research interest due to their diverse structural features and remarkable array of biological properties.

Objective: In the present study, we synthesized a series of 4-MU derivatives containing urea-piperazine and thioureapiperazine moieties and evaluated their antitumor activities to find efficacy antitumor drugs.

Method: Cell proliferation, apoptosis, cell cycle, the generation of reactive oxygen species and calcium were measured using MTT assay and flow cytometry, respectively. The expression of apoptosis- and proliferation-related proteins was determined by western blotting. The effect of 4l on apoptosis-related mRNA expression in NCI-H460 cells was detected by RT-PCR.

Results: Most of the target compounds exhibited potential anticancer activities against tested cancer cells but had low cytotoxicity to normal cells. Compound 4l inhibited the growth and proliferation of NCI-H460 cells and resulted in apoptosis. Successive studies conducted with 4l in NCI-H460 cells demonstrated that this compound induced the intracellular reactive oxygen species generation and calcium overload, suppressed nuclear factor-?B (NF-?B) activity and regulated anti- and pro-apoptotic proteins. In addition, compound 4l effectively arrested NCI-H460 cells in G2 phase and altered the cell cycle regulatory proteins especially cyclin B1.

Conclusion: Compound 4l exerts significant anticancer effects on NCI-H460 cells in vitro through targeting of mitochondria-dependent apoptotic pathway. These results indicate that the strategy for rational design of 4-MU derivatives may identify potential anticancer agents.


Colorectal, Prostate and Pancreas Human Cancers Targeted Bioassay-guided Isolations and Characterization of Chemical Constituents from Tephrosia apollinea by Loiy Elsir A. Hassan, Muhammad Adnan Iqbal, Saad S. Dahham, Yasser M. Tabana, Mohamed B. Khadeer Ahamed, Amin M.S. Abdul Majid (590-598).
Background: Cancer is characterized by uncontrolled cell division caused by dysregulation of cell proliferation. Therefore, agents that impair cancer cell proliferation could have potential therapeutic value. Higher plants are considered to be a good source of anticancer agents, and several clinically tested chemotherapeutic agents have been isolated from plants or derived from constituents of plant origin.

Methods: In the present study, a prenylated flavone (isoglabratephrin) was isolated from aerial parts of Tephrosia apollinea using a bioassay-guided technique. Chemical structure of the isolated compound was elucidated using spectroscopic techniques (NMR, IR, and LC-MC), elemental analysis and confirmed by using single crystal X-ray analysis. The antiproliferative effect of isoglabratephrin was tested using three human cancer cell lines (prostate (PC3), pancreatic (PANC-1), and colon (HCT-116) and one normal cell line (human fibroblast).

Results: Isoglabratephrin displayed selective inhibitory activity against proliferation of PC3 and PANC-1 cells with median inhibitory concentration values of 20.4 and 26.6 ?g/ml, respectively. Isoglabratephrin demonstrated proapoptotic features, as it induced chromatin dissolution, nuclear condensation, and fragmentation. It also disrupted the mitochondrial membrane potential in the treated cancer cells.

Conclusion: Isoglabratephrin could be a new lead to treat human prostate (PC3) and pancreatic (PANC-1) malignancies.


Y-shaped Folic Acid-Conjugated PEG-PCL Copolymeric Micelles for Delivery of Curcumin by Runliang Feng, Wenxia Zhu, Wei Chu, Fangfang Teng, Ning Meng, Peizong Deng, Zhimei Song (599-607).
Background: Curcumin is a natural hydrophobic product showing anticancer activity. Many studies show its potential use in the field of cancer treatment due to its safety and efficiency. However, its application is limited due to its low water-solubility and poor selective delivery to cancer.

Objective: A Y-shaped folic acid-modified poly (ethylene glycol)-b-poly (?-caprolactone)2 copolymer was prepared to improve curcumin solubility and realize its selective delivery to cancer.

Method and Results: The copolymer was synthesized through selective acylation reaction of folic acid with ?- monoamino poly(ethylene glycol)-b-poly(?-caprolactone)2. Curcumin was encapsulated into the copolymeric micelles with 93.71% of encapsulation efficiency and 11.94 % of loading capacity. The results from confocal microscopy and cellular uptake tests showed that folic acid-modified copolymeric micelles could improve cellular uptake of curcumin in Hela and HepG2 cells compared with folic acid-unmodified micelles. In vitro cytotoxicity assay showed that folic acid-modified micelles improved anticancer activity against Hela and HepG2 cells in comparison to folic acidunmodified micelles. Meanwhile, both drug-loaded micelles demonstrated higher activity against Hela cell lines than HepG2.

Conclusion: The research results suggested that the folic acid-modified Y-shaped copolymeric micelles should be used to enhance hydrophobic anticancer drugs' solubility and their specific delivery to folic acid receptors-overexpressed cancer.


Hybrid Benzoxazole-Coumarin Compounds Induce Death Receptor-Mediated Switchable Apoptotic and Necroptotic Cell Death on HN-5 Head and Neck Cancer Cell Line by Sahar Yaghmaei, Parichehr Ghalayani, Siamak Salami, Farahnaz Nourmohammadian, Soheila Koohestanimobarhan, Vahideh Imeni (608-614).
Background: Efficacy of multimodality approaches for the treatment of squamous cell cancer of the head and neck has remained unsatisfactory and further advances are critically required. Targeted cell death induction is a novel therapeutic approach that may help to improve clinical management of Head and Neck cancer patients.

Objective: The potency of novel hybrid benzoxazole-coumarins on the induction of apoptotic and/or necroptotic cell death were evaluated in a Head and Neck carcinoma cell line, HN-5, and a human skin cell line, AGO1522.

Methods: Quantitative toxicity of the synthesized compounds were elucidated by MTT assay, the specific activity of caspase-3 and -9 were measured by the colorimetric method and zVAD was used to block apoptosis. Expression of cell death related genes were studied using quantitative PCR.

Results: All three compounds were revealed IC50 value around 51.96±7.15 microM in HN-5 cells which were significantly lower than observed IC50 for AGO1522, 121.93±3.66 microM (p=0.001). Significant increase expression of FAS, FASL and TRIAL were observed in the treated cells with or without pretreatment with zVAD. In the absence of pretreatment, treatment lead to the induction of apoptosis with a significant increase in caspase-3 gene expression and caspase-3 activity without a significant increase in expression or activity of caspase-9 and other components of the intrinsic apoptotic pathway. However, in the zVAD pretreated cells, necroptotic cell death with a significant increase in expression of RIP1, RIP3, and MLKL genes was observed

Conclusion: The novel hybrid benzoxazole-coumarins effectively induce Caspase-3 dependent apoptosis in HN-5 cancer cells, but also could circumvent the blockage of apoptotic cell death by induction of necroptosis.


Physico-chemical and Biological Evaluation of Flavonols: Fisetin, Quercetin and Kaempferol Alone and Incorporated in beta Cyclodextrins by Danciu Corina, Florina Bojin, Rita Ambrus, Delia Muntean, Codruta Soica, Virgil Paunescu, Mirabela Cristea, Iulia Pinzaru, Cristina Dehelean (615-626).
Background: Fisetin,quercetin and kaempferol are among the important representatives of flavonols, biological active phytocomounds, with low water solubility.

Objective: To evaluate the antimicrobial effect, respectively the antiproliferative and pro apoptotic activity on the B164A5 murine melanoma cell line of pure flavonols and their beta cyclodextrins complexes.

Method: Incorporation of fisetin, quercetin and kaempferol in beta cyclodextrins was proved by scanning electron microscopy (SEM), differencial scanning calorimetry (DSC) and X-ray powder diffraction (XRPD). Pure compounds and their complexes were tested for antiproliferative (MTT) and pro-apoptotic activity (Annexin V-PI) on the B164A5 murine melanoma cell line and for the antimicrobial properties (Disk Diffusion Method) on the selected strains.

Results: The phytocompounds presented in a different manner in vitro chemopreventive activity against B164A5 murine melanoma cell line and weak antimicrobial effect.

Conclusion: The three flavonols: fisetin, quercetin and kaempferol were successfully incorporated in beta-cyclodextrin (BCD) and hydroxylpropyl-beta-cyclodextrin (HPBCD). Incorporation in beta cyclodextrins had a mix effect on the biological activity conducing to decrease, increase or consistent effect compared to pure phytocompound, depending on the screened process and on the chosen combination.


Background: Zanthoxylum capense (small knobwood) is a South African species known for a wide range of anecdotal uses. However, there is a dearth of information on its phytoconstitutional make-up, specifically its knobs, with only a few reports on the bioactive compounds that could justify its ethnomedicinal use.

Objectives: This work aimed to identify the active principles in Z. capense and evaluate their cytotoxicity against breast cancer tumor cells.

Method: Extracts from the stem bark, knobs and leaves were purified using chromatographic methods and characterized using spectroscopic techniques. Cytotoxicity of isolated compounds was evaluated on mammalian MCF-7, Caco-2 tumor cell lines and HEK295, a normal kidney cell line.

Results: The following compounds were isolated from the plant: a quaternary benzophenanthridine-type alkaloid (chelerythrine) along with its alkanoamine derivative (6-hydroxydihydrochelerythrine), an indolopyridoquinazoline alkaloid (rutaecarpine), an alkyl p-coumaric acid ester (dodecyl-trans-p-coumarate), a lignan (sesamin), a flavanol (catechin), two triterpenoids (lupeol and sitosterol) and two pigments (pheophytin a and lutein). In the cytotoxicity study, all tested samples decreased the viability of the MCF-7 tumor cells by at least 23% at concentration 1 μg mL-1 and Caco-2 tumor cells by at least 15% at concentration 5 μg mL-1 but a mild toxic effect on HEK295 across the tested samples.

Results: The following compounds were isolated from the plant: a quaternary benzophenanthridine-type alkaloid (chelerythrine) along with its alkanoamine derivative (6-hydroxydihydrochelerythrine), an indolopyridoquinazoline alkaloid (rutaecarpine), an alkyl p-coumaric acid ester (dodecyl-trans-p-coumarate), a lignan (sesamin), a flavanol (catechin), two triterpenoids (lupeol and sitosterol) and two pigments (pheophytin a and lutein). In the cytotoxicity study, all tested samples decreased the viability of the MCF-7 tumor cells by at least 23% at concentration 1 μg mL-1 and Caco-2 tumor cells by at least 15% at concentration 5 μg mL-1 but a mild toxic effect on HEK295 across the tested samples.


Construction of an Anticancer Fusion Peptide (ACFP) Derived from Milk Proteins and an Assay of Anti-ovarian Cancer Cells in vitro by Juan Zhou, Xue Yang, Wenxiao Zhang, Jing Wang, Cai Wei, Fang Gu, Ting Lei, Yide Qin (635-643).
Background: Some bioactive peptides derived from natural resources or synthesized by rational design have been shown to have very good anticancer effects. We designed an anticancer fusion peptide (ACFP) based on the structure of bovine lactoferricin (LfcinB) and hexapeptide (PGPIPN) derived from bovine milk protein.

Objective: To prepare ACFP through genetic engineering and study its antiovarian cancer activity.

Method: ACFP gene was produced by a flexible link arm connecting LfcinB and PGPIPN. ACFP was inductively expressed in Escherichia coli by the recombinant plasmid pGEX-KG-ACFP. ACFP was prepared and purified by affinity chromatography, and identified by polyacrylamide gel electrophoresis (PAGE), high-performance liquid chromatography (HPLC) and mass spectrometry (MS). Recombinant lentivirus vectors were produced by cotransfecting 293T cells with constructed plasmid pLJM1-ACFP, envelope plasmid ?8.91 and pVSVG using Lipofectamine. ACFP gene was transfected into ovarian cancer cells by pLJM1-ACFP lentivirus. Cell Viability was assayed by the methyl thiazolyl tetrazolium (MTT). The apoptosis of ovarian cancer SKOV3 cells was measured by flow cytometry and observed by Hoechst33258 staining.

Results: ACFP was successfully prepared and purified by genetic engineering. ACFP more effectively inhibited the viability of human ovarian cancer SKOV3 cells than the single parent peptides in vitro. ACFP was found to have no cytotoxicity towards untransformed cells. The ACFP gene in cancer cells infected with pLJM1-ACFP lentivirus could significantly inhibit the viability of SKOV3 cells and induce their apoptosis.

Conclusion: ACFP is a potential therapeutic agent for the treatment of ovarian cancer.