Anti-Cancer Agents in Medicinal Chemistry (v.16, #8)

Meet Our Editorial Board Member by Jose Correa-Basurto (933-933).

Chemical Structure Characteristics and Bioactivity of Small Molecule FAK Inhibitors by Fang-Yuan Cao, Xiao-Ping Zhou, Jing Su, Xiao-Hong Yang, Feng-Hui Mu, Jia-Yi Shen, Wei Sun (934-941).
Focal adhesion kinase (FAK) is a non-receptor tryosine kinase that plays a vital role in tumor cell survival, proliferation and migration. It has been shown that inhibiting the activity of FAK may result in impeding tumor cells invasion and growth. There are several small molecule FAK inhibitors which have been developed with outstanding FAK inhibitory activity. And most of the small molecules are nitrogen-containing aromatic compounds. This review describes the chemical structure characteristics and activity of current small molecule FAK inhibitors that aims to serve as a future reference for the development of potential FAK inhibitors.

Synthesis of Combretastatin A-4 Analogs and their Biological Activities by Agnieszka Siebert, Monika Gensicka, Grzegorz Cholewinski, Krystyna Dzierzbicka (942-960).
Combretastatin A-4 (CA-4) is a natural product, which consists of two phenyl rings, linked by an ethylene bridge. CA-4, inhibitor of polymerization of tubulin to microtubules, possesses a strong antitumor and anti-vascular properties both in vitro and in vivo. Previous studies showed that disodium phosphate salt of CA-4, a water-soluble prodrug is well tolerated at therapeutically useful doses. However, it should be noted that the cis-configuration of the double bond and the 3,4,5-trimethoxy group on ring A is necessary for the biological activity of CA-4. Structure of CA-4 renders the compound readily susceptible to isomerization, which reduces the potency and bioavailability. To circumvent this problem, a lot of scientists in the world synthesized a series of cis-restricted CA-4 analogs, where the double bond has been replaced by introduction of non-heterocyclic groups or heterocyclic groups like ? -lactam and oxadiazole. This paper reviews the most important approaches in analogs of combretastatin synthesis and presents structure-reactivity relationships for these compounds.

5'; Adenosine Monophosphate-Activated Protein Kinase Modulators as Anticancer Agents by Abhishek Thakur, Nirnoy Dan, Soumendranath Bhakat, Venkatesan Jayaprakash, Sugato Banerjee (961-972).
In spite of tremendous advancement in the field of cancer therapy, it is still one of the leading causes of death worldwide. One of the newest targets in the field of cancer therapeutics is 5'Adenosine Mono Phosphate activated protein kinase (AMPK). In vitro and in vivo evidences suggest anti-cancer activity of AMPK. AMPK activation may promote catabolism while preventing the anabolic processes of cell. Thus it may modulate cellular protein and lipid metabolism and affect the growth and division of cell. Here we review the mechanisms of action of AMPK modulators as future anti-cancer agents.

The metal-based drugs have gained increasing attention in the fight against cancer. Ga(III) in the form of inorganic salts has demonstrated efficacy in the treatment of a number of malignancies in experimental animals and humans, and has therefore attracted considerable pharmaceutical interest. However, the poor hydrolytic stability of Ga(III) in physiological medium owing to its property of hard Lewis acid prevents its widespread use in systemic cancer chemotherapy. Complexation of suitable chelators capable of stabilising Ga(III) against hydrolysis affords an opportunity for overcoming this drawback. Thiosemicarbazone (TSC) derivatives, a class of well-studied iron chelators featuring softer donor sulfur, also were evaluated to possess antineoplastic activities in an arrary of tumour cell lines. The structural modifications can affect the activities of TSCs, and related structure-activity relationships (SAR) have been studied over these years. Combination of Ga(III) and TSCs that are both pharmaceutically active has proved to exert synergistic effects of each component in one compound in most cases, and may produce more potent Ga(III) drugs. In this review, the SAR of ?(N)-heterocyclic thiosemicarbazone (HCT) analogues, a family of TSCs, were scrupulously surveyed, and the effect of Ga(III) complexation on their anticancer activity sparsely reported in literature was comparatively examined, in order to stimulate further advances in the field of gallium-based anticancer drugs.

In recent years, several small molecules approved by FDA for clinical studies are promising anti-cancer agent. Among the kinases, Abelson Leukaemia (Abl), sarcoma (Src), epidermal growth factor receptor (EGFR) and vascular endotelhial growth factor receptor (VEGFR) are considered as primary molecular targets for selective inhibition and the best successful targeted therapy of tyrosine kinase inhibitors (TKIs) has been achieved in the treatment of Bcr (break point cluster)-Abl leukemia.
The majority of type 1 kinase inhibitors target the active conformation of ATP binding site. In consequence of intensive studies on kinases, type 2, type 3 (allosteric) and type 4 (covalent) inhibitors have been discovered beyond the type 1 inhibitors. Although the selectivity is a major problem for type 1 inhibitors, these new type of inhibitors are promising for finding new selective compounds, which may provide other therapeutic options for cancer therapy. They may also be a solution to overcome drug resistance that remains unresolved yet. Threedimensional structural determination provides the development of specific and highly binding properties of compounds. Studying the prediction of a binding mode of inhibitors, homology model developments from kinase- ligand co-crystal structures and isosteric replacements have been used to improve binding properties of inhibitors. In this review, critical results related to the design strategies of kinase specifically targeted to Src and Bcr-Abl kinases and therapeutic potential of novel inhibitors will be evaluated. The readers will be endowed with the functional role of Src and Bcr-Abl kinases that lead inhibitor design, the structural analysis of binding modes of kinase inhibitors, the current progress in terms of therapeutic interventions and the mission of leading groups in the field.

Sirtuin Inhibitors: An Overview from Medicinal Chemistry Perspective by Yeong Keng Yoon, Chern Ein Oon (1003-1016).
The role of sirtuins in age-related diseases is an area of rapidly expanding investigation. Sirtuins are NAD+ -dependent class III histone deacetylases (HDACs) that share extensive homologies with the yeast HDAC Sir2. Class I and class II HDACs inhibitors have been identified as potential anticancer agents and are in clinical studies, but much less is known about class III HDAC inhibitors. However, inhibitors of sirtuins are currently being targeted as potential therapeutic agents for disease such as cancer, neurodegenerative disease and other disorders as sirtuins are discovered to regulate numerous downstream enzymes. Given the link between sirtuins and cancer, understanding the functionality of these enzymes may ultimately have significant impact in cancer prevention or cancer treatment. This review gives an updated overview regarding the regulation of sirtuin enzymes, their implications in cancer, various sirtuin inhibitor scaffolds and their insights in drug design.

Anticancer Vitamin K3 Analogs: A Review by Kirti D. Badave, Ayesha A. Khan, Sandhya Y. Rane (1017-1030).
Menadione (Vitamin K3) comprises of 1,4-naphthoquinone (NQ) moiety that can form redox isomers such as napthosemiquinone (NSQ) and catechol by accepting one or two electrons, respectively. The quinone redox cycling ability leads to the generation of "reactive oxygen species" (ROS) as well as arylation reactions, which are of biological relevance. This ability can be modulated with the help of suitable derivatization. A pharmacophore can be appended at suitable position of Vitamin K3 to have a synergistic or additive effect. In the present review, an attempt has been made to accrue such derivatives modified at 1 or 2 position and evaluated for their cytotoxicity activity on different series of human cancer cell lines such as HeLa, HL-60 and MCF- 7 etc. Production of reactive oxygen species (ROS) and mitochondrial dysfunction caused by Vitamin K3 derivatives leads to apoptosis and tumor inhibition. Recently, the CR-108 compound has shown to exhibit oxidative path together with non-oxidative phosphorylation of p38 MAP kinase in human breast cancer cells. Thus the chemical-biological interactions have been discussed which can be further extrapolated for the development of a potent anticancer drug.

New Pyrano[2,3-d:6,5-d']dipyrimidine Derivatives-Synthesis, in vitro Cytotoxicity and Computational Studies by Suresh Maddila, Kovashnee Naicker, Sridevi Gorle, Surjyakant Rana, Kotaiah Yalagala, Surya N. Maddila, Moganavelli Singh, Parvesh Singh, Sreekantha B. Jonnalagadda (1031-1037).
A new series of pyrano[2,3-d:6,5-d']dipyrimidine derivatives were synthesized and evaluated for their in vitro anticancer activity. The structures of all the synthesized compounds were confirmed by 1H NMR, 13C NMR, 15N NMR, HR-MS and FT-IR spectral analyses. The cytotoxic activities of these compounds against four human cancer (HeLa, SKBR-3, HepG2, and Caco-2) cell lines were determined. The synthesized compounds showed high selectivity, and four compounds (5e, 5f, 5g and 5i) showed excellent potent cytotoxicity against HeLa, SKBR-3, and HepG2 cancer cell lines. Furthermore, four other compounds (5a, 5c, 5b and 5d) have exhibited significant cytotoxicity activity in the SKBR-3 and HepG2 cell lines respectively, with moderate cytotoxicity seen in the HeLa cell line. Additionally, a molecular docking study was conducted to predict the anti-cancer behavior of the synthesized compounds via inhibition of the allosteric site of Human Kinesin Eg5.

Synthesis of Methotrexate Loaded Chitosan Nanoparticles and in vitro Evaluation of the Potential in Treatment of Prostate Cancer by Selvi Gunel Nur, Ozel Buket, Kipcak Sezgi, Aktan Cagdas, Akgun Cansu, Ak Guliz, Yilmaz Habibe, Biray Avci Cigir, Dodurga Yavuz, Hamarat Sanlier Senay (1038-1042).
The objective of the study was to investigate the cytotoxic and apoptotic effects of Methotrexate (MTX)-loaded chitosan (CS) on LNCaP prostate cancer cell line in vitro.
For this purpose, CS nanoparticles (NPs) were synthesized through ionic gelation method and MTX was loaded into the carrier with encapsulation. SEM images of the CS NPs have revealed that they have size of about 85 nm in mono-disperse manner. Drug loading yield was found to be 95.7 % with 470 ?g drug/mg NP loading capacity. In vitro drug release study showed that MTX was released in a controlled manner. Cell viability was detected by using trypan blue dye exclusion test and WST-1 cell proliferation assay was performed to show cytotoxic effects of the CS, the MTX and the MTX-loaded NP. IC50 values of CS, MTX and MTX-loaded NPs were assigned from the cell survival plot and were determined as 67.18 ?M, 20.21 ?M and 2.94 ?M at the 72nd hour, respectively. As for apoptosis analysis results, following to MTX-loaded CS treatment of LNCAP cells, apoptotic cell percent was detected as 39.3 % at the 72nd hour, that is, MTX-loaded CS induces 1.85-fold increase in apoptotic cell percent in comparison with that of MTX- induced apoptosis.

Cytotoxicity and Anti-proliferative Properties of Heterocyclic Compounds Derived from Progesterone by Rafat M. Mohareb, Nadia Y. Megally Abdo, Abeer A. Mohamed (1043-1054).
The following study explored the cytotoxic effect on human cancer cells of a series of novel progesterone derivatives through the synthesis of heterocyclic compounds incorporating progesterone moiety. The reaction of progesterone (1) with cyanoacetanilide derivatives gave the condensation products 3a,b. Either of compound 3a or 3b reacted with elemental sulfur affording the thiophene derivatives 4a and 4b, respectively. In addition, progesterone (1) underwent some multi-component reactions with aromatic aldehydes and cyanomethylene reagents in triethylamine to give the pyran derivatives 10a-f. Carrying the same reactions but using ammonium acetate afforded the pyridine derivatives 11a-f. The anti-tumor evaluations of the newly synthesized products were tested against six human cancer and normal cell lines. The results showed that nine compounds (3b, 7c, 10b, 10d, 10f, 11d, 13a, 13b and 14b) revealed optimal cytotoxic effect against cancer cell lines with IC50 ? 550 nM and their cytotoxicity's were higher than that of progesterone. Moreover, the toxicity of the most active compounds was measured against shrimp larvae. In addition, the anti-proliferative evaluations of these potent compounds were measured.

Guarana a Caffeine-Rich Food Increases Oxaliplatin Sensitivity of Colorectal HT-29 Cells by Apoptosis Pathway Modulation by Francine Carla Cadoná, Alencar Kolinski Machado, Verônica Farina Azzolin, Fernanda Barbisan, Eduardo Bortoluzzi Dornelles, Werner Glanzner, Paulo Bayard Dias Gonçalves, Charles Elias Assmann, Euler Esteves Ribeiro, Ivana Beatrice Mânica da Cruz (1055-1065).
We investigated the in vitro effects of guarana and its main metabolites (caffeine, theobromine and catechin) on cytotoxicity and cell proliferation on colorectal cancer (CRC) line HT-29 cells and on oxaliplatin sensitivity. The cells were exposed to different concentrations of guarana extract with and without oxaliplatin. The concentrations of bioactive molecules were also estimated considering their potential proportion on guarana hydro-alcoholic extract. Apoptosis effect was analyzed by annexin V quantification using flow cytometry, while apoptosis pathway gene modulation (p53, Bax/Bcl-2 genes ratio, caspases 8 and 3) was determined by qRT-PCR analysis. Cells exposed to guarana at a concentration of 100 ?g/mL presented a similar cytotoxic effect as HT-29 cells treated with oxaliplatin and did not affect the sensitivity of the drug. Guarana presented cell anti-proliferative effect and increased anti-proliferative oxaliplatin sensitivity at all concentrations tested here. Guarana was able to induce apoptosis and up-regulate the p53 and Bax/Bcl-2 genes.

The Synthetic Oleanane Triterpenoid HIMOXOL Induces Autophagy in Breast Cancer Cells via ERK1/2 MAPK Pathway and Beclin-1 Up-regulation by Natalia Lisiak, Ewa Toton, Blazej Rubis, Barbara Majer, Maria Rybczynska (1066-1076).
Autophagy is engaged in tumor growth and progression, but also acts as a cell death and tumor suppression initiator. Naturally-derived compounds and their derivatives constitute a rich source of autophagy modulators.
This paper presents the study on the mechanism of action of oleanolic acid derivatives, HIMOXOL and Br-HIMOLID, in MCF7 breast cancer cells. Both compounds reduced MCF7 cell viability more efficiently than the parental compound. It is noteworthy that this effect was specific to MCF7 cancer cells, while in non-cancer MCF-12A cells the cytotoxicity of the studied compounds was significantly lower. Moreover, in contrast to oleanolic acid, the tested compounds were only able to increase autophagy in MCF7 cells. Interestingly, HIMOXOL caused a significantly (p<0.05) higher autophagy rate in MCF7 cells than Br-HIMOLID, as measured by an LC3 immuno-identification study. We also found that HIMOXOL upregulated Beclin-1 expression in MCF7 cells. The observed biological activity of the compound contributed to the modulation of the MAPK ERK1/2 pathway that is engaged in the regulation of autophagy signaling. Importantly, we revealed no proapoptotic activity of the compound in the studied cells. However, autophagy induction in MCF7 cancer cells was reflected in the significantly decreased viability of these cells. Thus, we conclude that HIMOXOL (but not Br-HIMOLID) might reveal a significant potential against breast cancer cells, since it might efficiently induce the main autophagy mediator and prognostic factor, BECN1.