Targeted delivery of SN38 to breast cancer using amphiphilic diblock copolymers PHPMA-b-PBAEM as micellar carriers with AS1411 aptamer.

Breast cancer treatment can be challenging, but a targeted drug delivery system (DDS) has the potential to make it more effective and reduce side effects. This study presents a novel nanotherapeutic targeted DDS developed through the self-assembly of an amphiphilic di-block copolymer to deliver the chemotherapy drug SN38 specifically to breast cancer cells. The vehicle was constructed from the PHPMA-b-PEAMA diblock copolymer synthesized via RAFT polymerization. A single emulsion method was then used to encapsulate SN38 within nanoparticles (NPs) formed from the PHPMA-b-PEAMA copolymer. The AS1411 DNA aptamer was covalently bonded to the surface of the micellar NPs, producing a targeted DDS. Molecular dynamics (MD) simulation studies were also performed on the di block polymeric system, demonstrating that SN38 interacted well with the di block. The in vitro results demonstrated that AS1411- decorated SN38-loaded HPMA NPs were highly toxic to breast cancer cells while having a minimal effect on non-cancerous cells. Remarkably, in vivo studies elucidated the ability of the targeted DDS to enhance the antitumor effect of SN38, suppressing tumor growth and improving survival rates compared to free SN38.

Aptamer-based targeted delivery systems for cancer treatment using DNA origami and DNA nanostructures.

Due to the limitations of conventional cancer treatment methods, nanomedicine has appeared as a promising alternative, allowing improved drug targeting and decreased drug toxicity. In the development of cancer nanomedicines, among various nanoparticles (NPs), DNA nanostructures are more attractive because of their precisely controllable size, shape, excellent biocompatibility, programmability, biodegradability, and facile functionalization. Aptamers are introduced as single-stranded RNA or DNA molecules with recognize their corresponding targets. So, incorporating aptamers into DNA nanostructures led to influential vehicles for bioimaging and biosensing as well as targeted cancer therapy. In this review, the recent developments in the application of aptamer-based DNA origami and DNA nanostructures in advanced cancer treatment have been highlighted. Some of the main methods of cancer treatment are classified as chemo-, gene-, photodynamic- and combined therapy. Finally, the opportunities and problems for targeted DNA aptamer-based nanocarriers for medicinal applications have also been discussed.

Design and synthesis of a star-like polymeric micelle modified with AS1411 aptamer for targeted delivery of camptothecin for cancer therapy.

Improving of tumor targeting and decreasing side effects at normal cells of antitumor drugs are necessary to promote the cancer chemotherapy efficacy. Herein, we have synthesized a novel 21-arm star like diblock polymer of ß-cyclodextrin-{poly(ε-caprolactone)-poly(2-aminoethylmethacrylate)}21 which decorated with nucleolin aptamer (AS1411). The diblock polymer was prepared by combined ROP with electron transfer atom transfer radical polymerization (ARGET ATRP) methods followed camptothecin (CPT) encapsulation with high entrapment efficiency (65%). Subsequently, the attachment of AS1411 aptamer via covalent bond led to the formation of the final product ß-CD-(PCL-PAEMA)21/AS1411/CPT. In vitro drug release experiment demonstrated almost 50% of CPT was released in 72 h at acidic tumoral environment. The data of cellular toxicity (MTT) showed that the final product remarkably enhanced cell death in MCF-7 and 4T1 cells while normal cells (L929) showed high viability toward the prepared complex. Also, the finding of flow cytometry analysis and fluorescence imaging indicated successful internalization of complex into the target cells but not the nontarget cells. The in vivo experiments revealed the fact that ß-CD-(PCL-PAEMA)21/AS1411/CPT micelles showed high tumor inhibitory potential in comparison with free CPT. These findings exhibited the excellent ability of the novel star-like polymeric micelle with targeting agent for the targeted and effective delivery of CPT in cancer treatment.

Design, synthesis, and structure-activity relationship study of O-prenylated 3-acetylcoumarins as potent inhibitors of soybean 15-lipoxygenase.

In this work, the design, synthesis, and structure-activity relationships of a novel array of geranyloxy and farnesyloxy 3-acetylcoumarins were reported as potent soybean 15-lipoxygenase inhibitors. Among the prepared coumarins, 7-farnesyloxy-3-acetylcoumarin (12b) was found to be the most potent inhibitor by IC50  = 0.68 µM while O-geranyl substituents at positions 5 and 6 of 3-acetylcoumarin (10a and 11a) were not inhibitors. Using docking studies, the binding affinity and the preferred pose of synthetic compounds were considered. It was found that lipoxygenase inhibitory activity and prenyl length chain were directly related. The hydrophobic cavity of the enzyme was more effectively occupied by the farnesyl moiety of the potent inhibitor 12b rather than other derivatives. Also, with this pose of farnesyl chain in 7-farnesyloxy-3-acetylcoumarins, the acetyl group could be directed to the hydrophilic pocket in the active site.

O-prenylated 3-carboxycoumarins as a novel class of 15-LOX-1 inhibitors.

Allyloxy, Isopentenyloxy, geranyloxy and farnesyloxy derivatives of 3-carboxycoumarin, at position 5, 6, 7, and 8, were synthesized and their inhibitory potency against human 15-lipoxygenase-1 (human 15-LOX-1) were determined. Among the synthetic coumarins, O-allyl and O-isopentenyl derivatives demonstrated no considerable lipoxygenase inhibition while O-geranyl and O-farnesyl derivatives demonstrated potent inhibitory activity. 5-farnesyloxy-3-carboxycoumarin demonstrated the most potent inhibitory activity by IC50 = 0.74 µM while 6-farnesyloxy-3-carboxycoumarin was the weakest inhibitor among farnesyl analogs (IC50 = 10.4 µM). Bonding affinity of the designed molecular structures toward 15-LOX-1 3D structure complexed with RS75091, as potent 15-LOX-1 inhibitor, was studied by utilizing docking analysis. There was a direct relationship between lipoxygenase inhibitory potency and prenyl length chain. The ability of the prenyl portion to fill the lipophilic pocket which is formed by Ile663, Ala404, Arg403, Ile400, Ile173 and Phe167 side chains can explain the observed relationship. Similarity rate between the docked models and complexed form of RS75091, from point of view of configuration and conformation, could explain inhibitory potency variation between each prenyloxy substitution of 3-carboxycoumarins.

2-Prenylated m-dimethoxybenzenes as potent inhibitors of 15-lipo-oxygenase: inhibitory mechanism and SAR studies.

15-lipo-oxygenases are one of the iron-containing proteins capable of performing peroxidation of unsaturated fatty acids in animals and plants. The critical role of enzymes in the formation of inflammations, sensitivities, and some cancers has been demonstrated in mammals. The importance of enzymes has led to the development of mechanistic studies, product analysis, and synthesis of inhibitors. In this study, a series of allyl and prenyl dimethoxybenzenes were synthesized and their inhibitory potency against soybean 15-Lipo-oxygenase (L1; EC 1,13,11,12) was determined. Among the synthetic compounds, 2,6-dimethoxy-1-isopentenyl-4-methylbenzene, 2,6-dimethoxy-1-geranyl-4-methylbenzene, and 2,6-dimethoxy-1-farnesyl-4-methylbenzene showed the most potent inhibitory activity with IC50 values of 7.6, 5.3, and 0.52 µm, respectively. For some of the compounds, SAR studies showed acceptable relationship between inhibitory potency and enzyme-ligand interactions. Radical scavenging assessment results apart from the SAR studies indicate that electronic properties are the major factors for lipo-oxygenase inhibition potency of the mentioned compounds. Based on the theoretical studies, it was suggested that CH…O intramolecular hydrogen bond between ortho-methoxy oxygen and methine hydrogen atoms is one of the major factors in the stability of 2,6-dimethoxyallyl(or prenyl)benzenes radical via the planarity fixation between phenyl and allyl (or prenyl) pi orbitals.

15-Lipoxygenase inhibitors: a patent review.

INTRODUCTION: 15-Lipoxygenases (15-LOXes) are a family of iron-containing proteins that have the capability for unsaturated fatty acid peroxidation in animals and plants. Two types of the enzyme, 15-LOX-1 and 15-LOX-2, have been recognized in mammals to have different abilities in the peroxidation of arachidonic acid and linoleic acid. In mammalians, the critical role of the mentioned enzymes and their metabolites, hydroxyoctadecadienoic acid (HODE), lipoxins and eoxins, in the formation of inflammation, sensitivities, atherosclerosis and some cancers has been demonstrated. AREAS COVERED: This article reviews relevant publications and patents on 15-LOX inhibitors from the points of view of synthesis and biological activities. Herein, based on the chemical structure and pharmacophore moiety, 15-LOX inhibitors are categorized into heterocyclic, phenolic, allyl and allyloxy derivatives. EXPERT OPINION: It is noteworthy that to date no pharmaceutical product from 15-LOX inhibitors has been approved for therapeutic usage. Recently, the role of 15-LOX-1 in obesity, by directly relating 15-LOX-1 expression with the proliferation and hypertrophy of adipose cells, has been reported. Based on the role 15-LOX plays in promoting cancer by amplifying PPARγ transcription activity, however, it can be claimed that 15-LOX inhibitors will be deemed suitable as chemotherapy agents in the near future.

Synthesis and SAR studies of mono O-prenylated coumarins as potent 15-lipoxygenase inhibitors.

All of the mono isopentenyloxy, -geranyloxy and -farnesyloxy derivatives of coumarin were synthesized and their inhibitory potency against soybean 15-lipoxygenase (SLO) and human 15-lipoxygenase-1 (HLO-1) were determined. Amongst the synthetic analogs, 5-farnesyloxycoumarin showed the most potent inhibitory activity against SLO (IC(50) = 0.8 µM) while 6-farnesyloxycoumarin was the strongest HLO-1 inhibitor (IC(50) = 1.3 µM). The IC(50) variations of the farnesyl derivatives for HLO-1 (1.3 to ∼75 µM) were much higher than that observed for SLO (0.8-5.8 µM). SAR studies showed that hydrogen bonding, CH/π, anion-π and S-OC interactions with Fe(III)-OH, Leu408, Glu357 and Met419 were the distinct intermolecular interactions which can lead to important role of the coumarin substitution site in HLO-1 inhibitory potency, respectively.

Synthesis and SAR studies of 3-allyl-4-prenyloxyaniline amides as potent 15-lipoxygenase inhibitors.

15-Lipoxygenases are one of the nonheme iron-containing proteins with ability of unsaturated lipid peroxidation in animals and plants. The critical role of the enzymes in formation of inflammations, sensitivities and some of cancers has been demonstrated in mammalians. Importance of the 15-lipoxygenases leads to development of mechanistic studies, products analysis and synthesis of their inhibitors. In this work new series of the 3-allyl-4-allyoxyaniline amides and 3-allyl-4-prenyloxyaniline amides were designed, synthesized and their inhibitory potency against soybean 15-lipoxygenase were determined. Among the synthetic amides, 3-allyl-4-(farnesyloxy)-adamantanilide showed the most potent inhibitory activity by IC(50) value of 0.69 µM. SAR studies showed that in spite of prenyl length increases, the effects of the amide size and its electronic properties on the inhibitory potency became predominant. The SAR studies was also showed that the orientation of allyl and prenyloxy moieties toward Fe core of the SLO active site pocket is the most suitable location for enzyme inhibition.

Synthesis of new series of α-cyclodextrin esters as dopamine carrier molecule.

A new series of amphiphilic α-cyclodextrins were synthesized by grafting N-acylated amino acids [valine, leucine, phenylalanine, methionine, and tryptophan (3a-e)] to the primary hydroxyl groups via ester bond formation. The synthetic pathway involves selective hexa-bromination of the primary hydroxyls followed by per-substitution with the carboxylate moiety of the N-acetyl residues in the presence of DBU (1,8-diazabicyclo[5,4,0]undec-7-ene). The ability of the synthetic compounds for the extraction of dopamine was studied. The results showed a considerable ability of some of the amphiphilic compounds for the extraction of dopamine into octanol phase from water. To complete the study, the binding affinity of dopamine toward the synthetic host molecules was calculated by using of the molecular docking technique.

Synthesis and SAR comparative studies of 2-allyl-4-methoxy-1-alkoxybenzenes as 15-lipoxygenase inhibitors.

A group of 2-alkoxy-5-methoxyallylbenzene were designed, synthesised and evaluated as potential inhibitors of the soybean 15-lipoxygenase (SLO) on the basis of the eugenol and esteragol structures. Compound 4d showed the best half maximal inhibitory concentration (IC50) for SLO inhibition (IC50 = 5.9 ± 0.6 µM). All the compounds were docked in the SLO active site retrieved from the Research Collaboratory for Structural Bioinformatics (RCSB) Protein Data Bank (PDB entry: 1IK3) and showed that the allyl group of the synthetic compounds similar to the linoleic acid double bond, were oriented toward the Fe³+-OH moiety in the active site of the enzyme and this conformation was especially fixed by the hydrophobic interaction of the 2-alkoxy group with Leu5¹5, Trp5¹9, Val566 and Ile57². It was concluded that the molecular volume and shape of the alkoxy moiety was a major factor in the inhibitory potency variation of the synthetic compounds.