Targeting Notch signaling pathway to overcome drug resistance for cancer therapy

Chemotherapy is an important therapeutic strategy for cancer treatment and remains the mainstay for the management of human malignancies; however, chemotherapy fails to eliminate all tumor cells because of intrinsic or acquired drug resistance, which is the most common cause of tumor recurrence. Recently, emerging evidences suggest that Notch signaling pathway is one of the most important signaling pathways in drug-resistant tumor cells. Moreover, down-regulation of Notch pathway could induce drug sensitivity, leading to increased inhibition of cancer cell growth, invasion, and metastasis. This article will provide a brief overview of the published evidences in support of the roles of Notch in drug resistance and will further summarize how targeting Notch by “natural agents” could become a novel and safer approach for the improvement of tumor treatment by overcoming drug resistance.     

Therapeutic strategies of dual-target small molecules to overcome drug resistance in cancer therapy

Despite some advances in targeted therapeutics of human cancers, curative cancer treatment still remains a tremendous challenge due to the occurrence of drug resistance. A variety of underlying resistance mechanisms to targeted cancer drugs have recently revealed that the dual-target therapeutic strategy would be an attractive avenue. Compared to drug combination strategies, one agent simultaneously modulating two druggable targets generally shows fewer adverse reactions and lower toxicity. As a consequence, the dual-target small molecule has been extensively explored to overcome drug resistance in cancer therapy. Thus, in this review, we focus on summarizing drug resistance mechanisms of cancer cells, such as enhanced drug efflux, deregulated cell death, DNA damage repair, and epigenetic alterations. Based upon the resistance mechanisms, we further discuss the current therapeutic strategies of dual-target small molecules to overcome drug resistance, which will shed new light on exploiting more intricate mechanisms and relevant dual-target drugs for future cancer therapeutics.     

Metallobacteriochlorophylls as potential dual agents for photodynamic therapy and chemotherapy

A theoretical analysis of bacteriochlorophyll a containing its non-native divalent metal ions: Co, Ni, Cu, Zn, Ru, Rh, Pd, and Pt, has been carried out by means of density functional theory (DFT) calculations. The main stress was put on the derivatives with metals, which already found applications as coordination compounds in anti-tumor therapy (Ru, Pt, Pd, and Rh). The idea was to combine their cytotoxic properties with the known suitability of bacteriochlorophylls macrocycle for photodynamic therapy. The geometries of the studied systems are compared and reveal a number of similarities. The cores of the modified bacteriochlorophylls are flat, and the introduced metal ions lie in plane of the macrocycle, showing its large ability to accommodate metal ions of different sizes. However, four metal–nitrogen bonds, linking the central ions with the macrocycle ligand, are not equivalent. Metals are the strongest attached to nitrogens, which come from the pyrrole, which is fused with isocyclic ring. Based on the known spectroscopic data, the absorption properties of the proposed systems are predicted. Finally, it is found that all studied metal–macrocycle adducts are stable in aqueous media. The only exceptions are Mg-BChla (the finding is reflected by experimental facts) and Zn-BChla. The predicted high stability of Ru-, Rh-, Pt- and Pd-bacteriochlorophylls might turn out beneficial for therapeutic purposes.     

New 1,3-dioxolane and 1,3-dioxane derivatives as effective modulators to overcome multidrug resistance

Multidrug resistance (MDR) to antitumor agents represents a major obstacle to a successful chemotherapy of cancer. Overexpression of P-glycoprotein (p-gp) seems to be the major factor responsible for MDR. A large number of chemically unrelated compounds are known to interact with p-gp resulting in a decreasing resistance. In our efforts related to structure-activity studies of new potential MDR reversal agents we synthesized a series of compounds that differ in the aromatic core structure, the linker, and the basic moiety. For our search of new aromatic core structures we synthesized novel 2,2-diphenyl-1,3-dioxolane, 2,2- diphenyl-1,3-dioxane, and 4,5-diphenyl-1,3-dioxolane derivatives. A range of lipophilic linker structures and protonable basic moieties were synthesized and investigated to optimize the structure of the potential MDR-modulators. The compounds were tested in vitro using human Caco-2 cells. Both the cytotoxicity of the synthons and their ability to resensitize the cells were determined with a MTT assay. The results show that at low concentration various substances reverse tumor cell MDR. Some of the new structures show better effects than established modulators like trifluoperazine.     

Fragment-based modification of 2,4-diarylaminopyrimidine derivatives as ALK and ROS1 dual inhibitors to overcome secondary mutants

In order to explore novel ALK and ROS1 dual inhibitors capable of overcoming crizotinib-resistant mutants, two series of 2,4-diarylaminopyrimidine derivatives were designed, synthesized and evaluated for their in vitro cytotoxic activity. In this work, we retained the 2,4-diarylaminopyrimidine scaffold and derivatize the DAAP scaffold with sulfonyl and acrylamide moieties to extend the structure–activity relationship (SAR) study. To our delight, some compounds exhibited excellent inhibitory activity with a double-digit nanomolar level in MTT assay. Four compounds were selected for enzymic assays further, the results led to the identification of a potent ALK and ROS1 dual inhibitor X-17, with IC₅₀ values of 3.7 nM, 2.3 nM, 8.9 nM and 1.9 nM against ALK, ALK^L1196M, ALK^G1202R and ROS1, respectively. Ultimately, the molecular docking studies on X-17 clearly disclosed reasonable and optimal binding interactions with ALK.     

Glutathione transferases and development of new principles to overcome drug resistance

Chemoresistance is a multifactorial phenomenon and many studies clearly show that a coordinated expression of efflux transporter proteins and phase II conjugating enzymes in tumor cells is linked to the development of the multidrug resistance phenotype. In particular, the overexpression of glutathione S-transferases and efflux pumps in tumors may reduce the reactivity of various anticancer drugs. In recent years it has become evident that glutathione S-transferases are also involved in the control of apoptosis through the inhibition of the JNK signaling pathway. As such, the glutathione S-transferase superfamily has become the focus of extensive pharmaceutical research in attempt to generate more efficient anticancer agents. Here we present an overview of the GST inhibitors and the GST-activated pro-drugs utilized to date to overcome drug resistance.     

Synthesis and structure--activity analysis of novel dihydropyridine derivatives to overcome multidrug resistance

The structure activity relationships were studied on newly synthesized 1,4-dihydropyridine derivatives possessing a 1-pentyl group at the 4-position, and 3-pyridylpropylester was found to be one of the effective fragments for overcoming P-glycoprotein mediated multidrug-resistance (MDR) in cultured human cancer cells, in vitro. 3-Pyridylpropylester was also found to be one of the effective fragments for increasing the life span of P-glycoprotein overexpressing MDR P388 leukemia-bearing mice, in vivo. All compounds had weak calcium antagonistic activities, but there appeared no relationship between MDR reversing effect and calcium antagonistic activity.     

Anti-AIDS agents. Part 57: Actein, an anti-HIV principle from the rhizome of Cimicifuga racemosa (black cohosh), and the anti-HIV activity of related saponins

Actein (1), a tetracyclic triterpenoid from the rhizome of Cimicifuga racemosa (black cohosh), and 82 related triterpenoid and steroidal saponins isolated from higher plants were evaluated for anti-HIV activity as a continuing study to discover potential anti-AIDS agents from natural products. Actein showed potent activity and another twelve saponins showed moderate activity. The active compounds included two steroidal, seven tetracyclic triterpenoid, and four pentacyclic triterpenoid compounds.     

Anti-AIDS agents 66: syntheses and anti-HIV activity of phenolic and aza 3',4'-di-O-(-)-camphanoyl-(+)-cis-khellactone (DCK) derivatives

New phenolic and aza 3',4'-di-O-(-)-camphanoyl-(+)-cis-khellactone (DCK) analogs were synthesized and assayed for inhibition of HIV-1 IIIB replication in H9 lymphocytes. Compound 16, 4-methyl-1'-aza-DCK (4-methyl-aza-DCK), was less lipophilic than 4-methyl-DCK, and retained sub-micromolar anti-HIV activity with EC(50) and TI values of 0.77 microM and >42, respectively. Moreover, it showed moderately improved metabolic stability. Introduction of phenolic hydroxyl groups to 4-methyl-DCK decreased lipophilicity significantly, but did not improve metabolic stability and also decreased activity.     

Novel drug designing approach for dual inhibitors as anti-inflammatory agents: implication of pyridine template

Compounds incorporating thiophene moiety, a pi excess five membered heterocycle, have attracted a great deal of research interest, owing to the therapeutic utility of the template as useful drug molecular scaffolding. We report the synthesis and pharmacological evaluation of thiophenes substituted with 4-methanesulfonyl benzoyl moiety at the fifth position of the ring, as possible anti-inflammatory lead candidates. The aryl sulfonyl methyl thiophene analogs AP29, AP82, and AP37, when screened for anti-inflammatory activity in carrageenin induced rat paw edema, an acute in vivo model, exhibited moderate to good activity at a dose level of 100 mg/kg body weight P.o compared to Ibuprofen. In a five day formalin induced rat paw edema, a chronic in vivo anti-inflammatory model, candidates AP29, AP82, and AP37 inhibited the disease progression by 53%, 34%, and 65%, respectively on the fifth day, at a dose level of 100 mg/kg body weight P.o compared to Rofecoxib, Ibuprofen, and Dexamethasone at therapeutic doses which gave a protection of 53.8%, 81.5%, and 81.5%, respectively. The replacement of the 4-methanesulfonyl benzoyl moiety in AP82 with the pyridine template, 3,5-dimethyl-4-methoxy-2-pyridyl function, gave rise to AP84, which was less active in the acute model, but gave 54% and 75% protection both during the first day and fifth day, respectively, in the chronic model. A dual mechanism of action is proposed for AP84, a non-steroidal drug which has exhibited remarkable activity when compared to the steroid dexamethasone. These results open up new avenues in designing novel anti-inflammatory drugs as dual inhibitors with the incorporation of a pyridine template as part of the pharmacophore.     

Anti-AIDS agents. Part 56: Synthesis and anti-HIV activity of 7-thia-di-O-(-)-camphanoyl-(+)-cis-khellactone (7-thia-DCK) analogs

Two thia-DCK analogs (3a,b) were synthesized and evaluated for inhibition of HIV-1 replication in H9 lymphocytes. Compound 3a showed potent anti-HIV activity with an EC₅₀ value of 0.14 μM and a therapeutic index of 1110. However, the corresponding 6-tert-butyl-substituted compound (3b) showed no suppression. The bioassay results indicated that thia-DCK analogs merit attention as potential HIV-1 inhibitors.     

Anti-AIDS agents. Part 58: synthesis and anti-HIV activity of 1-thia-di-O-(-)-camphanoyl-(+)-cis-khellactone (1-thia-DCK) analogues

Two 1-thia-DCK analogues (9a and 9b) were synthesized and evaluated for inhibition of HIV-1 replication in H9 lymphocytes. Compound 9a showed excellent anti-HIV activity with an EC(50) value of 0.00012 microM and therapeutic index of 1408000. Compound 9b was less active with EC(50) and TI values of 3.11 microM and 62.3, respectively. The bioassay results indicated that thia-DCK analogues merit attention as potential HIV-1 inhibitors.     

Identification of a series of tetrahydroisoquinoline derivatives as potential therapeutic agents for breast cancer

A series of tetrahydroisoquinoline-N-phenylamide derivatives were designed, synthesized, and tested for their relative binding affinities, and antagonistic activities against estrogen receptor (ER). Compound 1f (relative binding affinity, RBA=5) showed higher binding affinity than tamoxifen (RBA=1), a potent ER antagonist and currently being used for breast cancer therapy. Compound 1f also exerted optimal antagonistic activity against ER in reporter and cell proliferation assays. Interestingly, compound 1j, which only has a minor agonistic effect against ER, acted as a progesterone receptor (PR) antagonist and exerted agonistic activity against AP-1 through ER pathway. Our results show that these new compounds can be employed as leading pharmacophore for further development of potent selective ER and/or PR modulators or antagonists.     

Anti-AIDS agents. Part 47: Synthesis and anti-HIV activity of 3-substituted 3',4'-Di-O-(S)-camphanoyl-(3'R,4'R)-(+)-cis-khellactone derivatives

Six 3-substituted 3',4'-di-O-(S)-camphanoyl-(+)-cis-khellactone derivatives (3-8) were synthesized from 3-methyl DCK (2). 3-Hydroxymethyl DCK (6) exhibited potent anti-HIV activity in H9 lymphocytes with EC(50) and TI values of 1.87 x 10(-4) microM and 1.89 x 10(5), respectively. These values are similar to those of DCK and better than those of AZT in the same assay.     

Design and synthesis of quinazolinones as EGFR inhibitors to overcome EGFR resistance obstacle

The epidermal growth factor receptor (EGFR) T790M mutant is found in about 50% of clinically acquired resistance to gefitinib among patients with non-small cell lung cancer (NSCLC). New derivatives of 4(3H)-quinazolinones were synthesized and evaluated for their inhibitory activity against NSCLC. The results of the study demonstrated that compound 79, 7-chloro-3-(5-(4-methoxyphenyl)-1,3,4-thiadiazol-2-yl)-2-phenylquinazolin-4(3H)-one was found to be the most potent compounds of the series with IC₅₀ value of 0.031 μM against mutant T790M/L858R EGFR. Compounds 15, 51, 73, 75, 78, 79 and 96 were less potent against A549 (WT EGFR and k-Ras mutation) and HT-29 (non-special gene type) cells, showing a high safety index. The obtained results showed that compounds 15, 51, 73, 75, 78, 79 and 96 could be the promising template to overcome drug resistance mediated by the EGFR T790 Mutant.     

Syntheses of benzoquinolizidine and benzoindolizidine derivatives as anti-amnesic agents.

Tacrine, one of the drugs available for Alzheimer's disease based on the cholinergic approach, suffers from considerable toxicity. Many analogues of tacrine have been prepared which retain the pharmacologically rich aminopyridine or aminoquinoline motifs. The current research was undertaken to produce an acetylcholinesterase inhibitor by employing 11-aminobenzoquinolizidines (4) and 10-aminobenzoindolizidines (5) as templates. Thus, we aimed to achieve three goals relative to tacrine: eliminate the pyridine and quinoline moieties and render the molecule less flat. Overall, the compounds we prepared were poorer inhibitors of acetylcholinesterase compared to tacrine. The single exception was compound 6f which exhibited an effect comparable to that of tacrine, but only at a dose of the order of 10(-3) M. However, despite the poor acetylcholinesterase inhibition by 6b, this compound proved to be an effective anti-amnesic agent at 45 mg/kg dose.     

Design and synthesis of tetrahydroisoquinoline derivatives as potential multidrug resistance reversal agents in cancer

Exploration for new MDR-modulator utilizing tetrahydroisoquinoline as scaffold disclosed 6,7-dimethoxy-1-(3,4-dimethoxy)benzyl-2-(N-n-octyl-N'-cyano)guanyl-1,2,3,4-tetrahydroisoquinoline (7) as a readily accessible medicinal lead. Compound 7 possessed potent MDR reversal activity in the range of the reference compound verapamil, and had not cardiovascular activity compared to verapamil.