Letters in Drug Design & Discovery - Volume 17, Issue 4, 2020

Background: Chemotherapy is the most important treatment method against cancer, in addition to surgery and radiotherapy. However, Multidrug Resistance (MDR) in cancer always results in the failure of chemotherapy. Effective chemotherapy agents need to be delivered efficiently, distributed mostly in the tumor tissue, and highly internalized by tumor cells to eventually inhibit proliferation or promote death of the tumor cells. A growing number of studies have indicated that any defects that emerge during these steps could contribute to the occurrence of MDR in tumors. Carbon Nanotubes (CNTs) are newly developed biocompatible materials that can be designed to deliver anticancer agents by functionalizing the CNTs with drugs. Enhanced drug delivery efficiency and improved treatment efficacy have been observed through CNT-based drug delivery systems. However, some reports have shown that the simple administration of CNTs can reverse MDR in cancer and enhance chemotherapy efficacy without anticancer agents attached to the surface of the CNTs. Objective: Through an extensive review of previous reports in regard to CNTs and chemotherapy, this paper aims to identify the various mechanisms of CNTs that inhibit MDR in cancer and enhance chemotherapy sensitivity. Results: CNTs can increase the antitumor effects of chemotherapy agents. CNTs can not only increase drug delivery accuracy and efficiency but also promote drug uptake, decrease drug efflux, improve tumor hypoxia conditions, and induce autophagy and apoptosis in tumor cells, which make the tumor more sensitive to antitumor agents.

Background: Phage display is a biotechnological technique that presents peptides with coated proteins on the surface of phage. In the last two decades, growing applications of phage display in various fields of biotechnology have been investigated. Phage display libraries allow to present billions of peptides on phage surface for selection of a specific peptide with the desired affinity. Objective: In this regard, high-affinity phage antibodies against tumor antigens are produced and applied for diagnosis and treatment of cancer. Methods: Moreover, phage display libraries are employed to select the high affinity T Cell Receptors (TCRs) for the peptide-MHC complex which is an attractive approach in cancer immunotherapy. Due to immunogenic properties of phage particles, phage-based vaccines do not require adjuvant, in addition the phage particles can effectively take up by Antigen Presenting Cells (APCs). Results: Taken together, phage-based cancer vaccines are ideal candidates that provide a key for eradication of tumor cells. Conclusion: In this review, we focus on various applications of a phage display platform in different types of cancer immunotherapy approaches.

Background: The family of serine/threonine protein kinases is associated with peculiar tumor cell-cycle checkpoints which are overexpressed in proliferating tissues as well as in cancers, making them as potential targets for cancer chemotherapy. In the present paper, 3D-QSAR studies were carried out on 4,5-dihydro-1H-pyrazolo[4,3-h]quinazolines against serine/threonine protein kinases viz. polo-like 1 (Plk-1), cyclin dependent 2/A (CDK2/A) and Aurora-A (Aur-A) and their in vitro anti-proliferative activity on A2780 ovarian cancer cell line. Methods: 3D-QSAR models were derived using stepwise forward-backward partial least square (SWFB_PLS) regression method using VlifeMDS QSAR plus software and the docking calculations were carried out using Docking Server. Results: The derived statistically significant and predictive 3D-QSAR models exhibited correlation coefficient r2 in the range of 0.875 to 0.966 and predictive r2 in the range of 0.492 to 0.618. The hydrogen bond donor NH group joining the phenyl ring with quinazoline and terminal amide group were found to favored for Plk-1, CDK2/A and anti-proliferative activity. Estimated energy of binding of compound 45 with enzymes was in the range of -8.52 to -9.03. Conclusion: The results of 3D-QSAR studies may be useful in the development of new pyrazolo[ 4,3-h]quinazoline derivatives with better inhibitory activities against serine/threonine kinases.

A series of new α-aminophosphonates containing potential anticancer active 4-chloro-6- methylpyrimidin-2-amino pharmacophore were synthesized. Background: α-Aminophosphonates are of growing interest to the researchers due to their biological activities. Besides aminophosphoryl functionality, which is responsible for the vital activity, incorporation of a captivating pharmacophore on it will definitely enrich its activity. Objective: Erstwhile many of the reported α-aminophosphonates impregnated with bioactive heterocycles like quinazoline, chromene, pyrazole, furan and thiophene were used as anticancer drugs, and we are intended to enhance the anticancer potentiality of α-aminophosphonates by substituting a new 4-chloro-6-methylpyrimidin-2-yl group into its structure, specifically on nitrogen atom. Methods: Title compounds were synthesized by Kabachnik-Fields reaction by using sulfated Titania, a solid acid catalyst that is encompassed with high density of Lewis acidic reaction sites. The series of synthesized compounds were screened for in vitro anti-cancer activity and their ADMET, QSAR and drug properties studied. Results: Structures of all the title compounds synthesized in high yields were confirmed by spectral & elemental analyses. Their anti-cancer screening studies on various cell lines and evaluation of other properties revealed their potentiality towards the inhibition of growth of DU145 & A549 cell lines. Conclusion: The substitution of 4-chloro-6-methylpyrimidin-2-amino moiety on to the amino functionality of the α-aminophosphonates is a critical task invariably due to the substitutions that are located on α-carbon. As such, this substitution had increased the scope for growth inhibition of DU145 and A549 cancer cells.

Background: Previous identification of N,N-diethylthiobarbiturates as potential α-glucosidase inhibitory potential prompted us to investigate the antiglycation activity of these synthetic compounds (1-25) in order to identify the lead candidates for their possible antidiabetic potential. Methods: Synthetic compounds (1-25) were evaluated for their antiglycation activity using Bovine Serum Albumin assay (BSA). Result: Compounds exhibited varying degree of inhibition in the range of IC50 = 61.16 ± 2.3 - 656.71 ± 2.5 μM as compared to the standard rutin (IC50 = 294.5 ± 1.50 μM). Among the twenty five synthetic molecules, seven compounds showed good activity in comparison with the standard. Compound 4 (IC50 = 61.16 ± 2.3 μM) having hydroxy substituents was the most active molecule of the library. This study revealed that compound 4 has dual acting antidibetic molecule. Conclusion: In conclusion, the synthetic N,N-diethylthiobarbiturates can act as lead molecules. Furthermore, synthetic variations on N,N-diethylthiobarbituric acid moiety might be helpful in generating a library of potential anti diabetic agent. Especially, compound 4 has been identified as dual acting antidiabetic agent i.e. α-glucosidase inhibitor and antiglycating agent.

Background: A series of eighteen 2-Oxo-N-substituted phenyl- 2H-chromene-3- carboxamide analogues has been evaluated for HIV-1 integrase (IN) inhibition. Methods: The derivatives were synthesized via a two-step pathway commencing with 2- hydroxybenzaldehyde and diethyl malonate followed by hydrolysis of ester and coupling with various aromatic amines. The HIV-1 IN inhibitory potential of these compounds has been studied relative to dolutegravir, a known HIV-1 IN inhibitor using a standard available kit. Results: Six molecules (compounds 13h, 13i, 13l, 13p to 13r) showed significant inhibition of HIV- 1 integrase 3′-strand transfer with IC50 values less than 1.7 μM. The presence of chromene-3- carboxamide motif was shown to be crucial for the enzymatic activity. In addition, molecular modelling studies were also done to justify the IN inhibition and in vitro-in silico correlation was drawn. Conclusion: However, these compounds did not show HIV-1 and HIV-2 inhibition below their cytotoxic concentration indicating that these compounds cannot be taken further for anti-HIV activity as such and require structural modification.

Background: Giardiasis is an important public health problem. However, its pharmacological treatment is limited mainly to two drugs, metronidazole and nitazoxanide. Objectives: Screening four series of esters (methyl, ethyl, isopropyl and n-propyl) of quinoxaline-7- carboxylate 1,4-di-N-oxide in in vitro and in vivo models as antigiardiasis agents. Methods: Briefly, 4 × 104 trophozoites of G. lamblia were incubated for 48 h at 37 °C with different concentrations of esters of quinoxaline-7-carboxylate 1,4-di-N-oxide, albendazole, metronidazole and nitazoxanide. Afterwards, trophozoites were counted and the half maximal inhibitory concentration (IC50) was calculated by Probit analysis. The in vivo antigiardial activity of the compounds was demonstrated using experimental infections of G. lamblia in suckling female CD-1 mice. Results: Compound T-069 with a thienyl, a trifluoromethyl and an isopropyl group at R1-, R2- and R3-position, respectively, on the quinoxaline 1,4-di-N-oxide ring in an in vitro model showed an IC50 value of 0.0014 μM, and 3502 and 1108 times more giardicidal activity than nitazoxanide and metronidazole in an in vivo model. Conclusion: Isopropyl ester of quinoxaline-7-carboxylate 1,4-di-N-oxide derivatives showed better giardicidal activity than the reference drugs; therefore, these compounds are good candidates to develop new pharmacological treatment for giardiasis.

Background: 1,3,4-thiadiazole is a lead molécule which is versatile for a wide variety of biological activities and in continuation of our interest in establishing some novel heterocyclic compounds for antitumor activity. Objective: The objective of the study was to synthesize series of 5-(1,3-benzodioxol-5-yl)-1,3,4- thiadiazol-2-amine derivative and evaluated for their possible in vitro and in vivo anticancer activity. Methods: The synthesis of 2-aminonaphthoxy-1,3,4-thiadiazole and 5-(1,3-benzodioxol-5-yl)-1,3,4- thiadiazol-2-amine as intermediates were carried out by cyclization method. A mixture of thiosemicarbazide and naphthoxyacetic acid/piperonylic acid and phosphoryl chloride were subjected to cyclization with phosphorous oxychloride to obtain compound 3. Further compounds 1 and 3 were reacted with different aromatic aldehydes in methanol to form compounds 2a-e and 4a-e. The compounds 2a-e and 4a-e were characterized for the melting points, IR, Proton NMR and Mass spectra. The compounds were further evaluated for their anticancer activity. The docking study was performed using Discovery studio 4.1 (Accelrys) software against DNA-binding domain of STAT3. The compounds were analyzed for the ligand-protein binding interaction(s) by molecular docking into the active site of STAT3β using the CDOCKER protocol of Discovery studio (v4.1). Results: The title compounds were screened for in vitro anticancer on human breastadenocarcinoma cells (MCF-7 and Vero). Compounds 4c, 4d and 2d against MCF 7 and 4d against Vero cell lines were found to be the most active dérivatives with IC50 values of 1.03, 2.81 and 3.45 μg/ml against MCF 7 and 31.81 μg/ml against Vero cell lines, respectively. Conclusion: From the in vivo anticancer studies, it was concluded that the synthesized compounds 4c and 4d displayed anticancer activity comparable to the standard drug, while the rest of the compounds demonstrated mild potency for anticancer studies.

Background: An elucidation study was carried out to evaluate 19 different methylthiomorpholine, methylmorpholine and piperidine compounds as possible inhibitors of the Angiotensin Converter Enzyme (ACE) using as a positive blank: Captopril, drug used as an antihypertensive agent and known for its biological effect over ACE. Also, the interaction using Hippuryl-histidyl-leucine (HHL) as an artificial substrate was simulated. Methods: The study was made using the Molecular Operating Environment (MOE), SYBYL and Gaussian software. Results: All the molecular recognition process was performed under the conditions reported for such interaction, in order to emulate the experimental parameters as close as is possible to a real system. Conclusion: After the calculations the best candidates for the ACE inhibition were determined.

Background: Heat Shock Protein 90(HSP90) inhibitors are involved in multiple anticancer pathways, which indicate many important novel molecular targets for cancer therapy. However, the characteristics of poor water solubility, liver toxicity and finite bioavailability of the present inhibitors limit clinical application. Hence, it is crucial to evaluate the characteristics of compounds and develop new drugs with hypotoxicity and high-bioactivity. Methods: Quantitative Structure-Activity Relationship (QSAR) has been an effective method for screening novel structures and predicting various properties of the synthesized compounds. Heuristic Method (HM) and Gene Expression Programming (GEP) algorithm were used to establish linear and nonlinear models severally. Results: The results showed that HM has good correlation coefficients of R2 and lower S2 as 0.79 and 0.29 for the training set and GEP has better values of 0.89 and 0.05, respectively. Conclusion: Both models have the capability of prediction but the nonlinear model developed by GEP has a more excellent predictive ability and indicates further optimization of the HSP90 inhibitors.

Background: Jejunum is one of the most radiosensitive parts of the gastrointestinal system. This is the main issue, leading to several side effects to patients with abdominal cancers, in addition to affecting their quality of life. Epithelial layer and clonogenic cells in the jejunum are the most sensitive parts of the intestine, while damage to vascular may lead to chronic inflammation and bleeding. Both melatonin and metformin have shown abilities to attenuate radiation toxicities through the modulation of DNA damage responses, neutralization of free radicals and alleviation of inflammation. In this study, we aimed to evaluate the possible radioprotective effects of melatonin and metformin when administered either alone or as a combination, in rat’s jejunum against a high dose of radiation. Methods: 40 male rats were divided into 8 groups as G1: control; G2: metformin; G3: melatonin; G4: melatonin + metformin; G5: radiation; G6: radiation + melatonin; G7: radiation + metformin; G8: metformin + melatonin + radiation. Rats were irradiated with 10 Gy gamma rays, while treatments were administered at 100 mg/kg. The ratio for melatonin and metformin was 1:1. 3.5 days after irradiation, all rats were sacrificed, followed by histopathological evaluation of the jejunum. Results: This study showed that whole body irradiation of rats led to severe injuries to the epithelial and vascular of jejunum. A single administration of either melatonin or metformin was unable to mitigate radiation toxicity. However, administering the combination of melatonin and metformin could mildly mitigate radiation-induced jejunum injury. Conclusion: From the results of this study, we suggest that the combination of melatonin and metformin has superior radioprotective effect for jejunum compared with the single administration of these drugs.

Background: A wide range of pyrazole derivatives gained special attention due to their wide range of pharmacological activities especially the therapeutic activities. Many pharmacological drugs containing the pyrazole nucleus are known in the market. Methods: The 3-phenyl-1H-pyrazol-5(4H)-one was the key starting compound for many heterocyclic reactions to produce substituted and fused pyrazole derivatives. Results: Antiproliferative activities of the produced compounds against six cancer cell lines A549, HT-29, MKN-45, U87MG, and SMMC-7721 and H460 were measured through which compounds showed high inhibitions. The most promising compounds were tested against tyrosine kinases (c-Kit, Flt-3, VEGFR-2, EGFR, and PDGFR). Structure-Activity Relationship (SAR) was rationalized by looking at the varying structural features of the molecules. In addition, the most active compounds were selected for Pim-1 inhibition. Conclusion: Thirty-nine pyrazole derivatives were synthesized. Nine of them 8b, 9, 12b, 12d, 14b, 15b, 18d, 18f, 19b, and 21d were the most active compounds toward the selected cancer cell lines. Compounds 12b, 14b, 18d, 18f, and 21d showed high inhibitions toward the tyrosine kinases, whereas compounds 14b, 18d, and 18f were the most potent inhibitors of Pim-1.

Background: Several series of hydrazone derivatives of pyrazole-4-carboxaldehydes (4- 11) were designed and synthesized to screen their inflammatory activity. Methods: The products were characterized by 1H NMR, 13C NMR and HRMS. In vitro LPS-induced TNF-α model and in vivo xylene-induced ear-edema model were used to evaluate their antiinflammatory activity. Results and Conclusion: Bioassays indicated that most of the compounds markedly inhibited the expression of TNF-α at the concentration of 10 μg/mL. Compounds 7b and 11c, two of the most potent compounds, exhibited TNF-α inhibitory ability in a dose-dependent manner with IC50 values of 5.56 and 3.69 μM, respectively. In vivo, intraperitoneal administration with 7b and 11c markedly inhibited the ear edema at the doses of 20 and 50 mg/kg. Compound 11c, inhibited edema by 49.59 % at the dose of 20 mg/kg, was comparable to the reference drug dexamethasone at the same dose (with an inhibition of 50.49 %). To understand the binding pattern, molecular docking of representative 7b and 11c was performed, which demonstrated that both compounds have a forceful binding with the TNF-α, and that the phenyl and hydrazide moieties of them play a significant role in binding with the target site.

Background: Chemotherapy is one of the mainstays of cancer treatment, despite the serious side effects of the clinically available anticancer drugs. In recent years increasing attention has been directed towards novel agents with improved efficacy and selectivity. Compounds with chalcone backbone have been reported to possess various biological activities such as anticancer, antimicrobial, anti-inflammatory, analgesic, antioxidant, etc. It was reported that aminomethylation of hydroxy chalcones to the corresponding Mannich bases increased their cytotoxicity. In this context, our interest has been focused on the design and synthesis of the so-called multi-target molecules, containing two or more pharmacophore fragments. Methods: A series of Mannich bases were synthesized by the reaction between 6-[3-(3,4,5- trimethoxyphenyl)-2-propenoyl]-2(3H)-benzoxazolone, formaldehyde, and a secondary amine. The structures of the compounds were confirmed by elemental analysis, IR and NMR spectra. The new Mannich bases were evaluated for their in vitro cytotoxicity against a panel of human tumor cell lines, including BV-173, SKW-3, K-562, HL-60, HD-MY-Z and MDA-MB-231. The effects of selected compounds on the cellular levels of glutathione (GSH) were determined. Results: The new compounds 4a-e exhibited concentration-dependent cytotoxic effects at micromolar concentrations in MTT-dye reduction assay against a panel of human tumor cell lines, similar to those of starting chalcone 3. The tested agents led to concentration - dependent depletion of cellular GSH levels, whereby the effects of the chalcone prototype 3 and its Mannich base-derivatives were comparable. Conclusion: The highest chemosensitivity to the tested compounds was observed in BV- 173followed by SKW-3 and HL-60 cell lines.