Twin Drug Research Articles

Self-Assembled Nanoparticles of Amphiphilic Twin Drug from Floxuridine and Bendamustine for Cancer Therapy

We report here an amphiphilic twin drug strategy directly using small molecular hydrophilic and hydrophobic anticancer drugs to self-assemble into nanoparticles with a high and fixed drug content, which can solve problems of anticancer drug delivery including poor water solubility, low therapeutic indices, and severe side effects. The twin drug has been prepared by the esterification of the hydrophilic anticancer drug floxuridine (FdU) with the hydrophobic anticancer drug bendamustine (BdM). Due to its inherent amphiphilicity, the FdU-BdM twin drug can self-assemble into stable and well-defined nanoparticles. After FdU-BdM twin drug enters into cells, the ester linkage between hydrophilic and hydrophobic drugs is readily cleaved by hydrolysis to release free FdU and BdM. Since both FdU and BdM can kill cancer cells, the FdU-BdM twin drug nanoparticles can overcome the multidrug resistance (MDR) of tumor cells and present an excellent anticancer activity. This strategy can be extended to other hydrophilic and hydrophobic anticancer drugs to synthesize amphiphilic twin drugs which can form nanoparticles to self-deliver drugs for cancer therapy.

Synthesis of the Twin Drug of Ibuprofen and Paracetamol

Synthesis of the Twin Drug of Ibuprofen and Paracetamol

Enhancement of neighbouring-group participation in Cu0-promoted cross-coupling gem-difluoromethylenation of aryl/alkenyl halides with 1,3-azolic difluoromethyl bromides.

A copper(0)-promoted direct reductive gem-difluoromethylenation of unactivated aryl or alkenyl halides with benzo-1,3-azolic (oxa-, thia- or aza-) difluoromethyl bromides or 2-bromodifluoromethyl-1,3-oxazoline has been developed for the construction of pharmaceutically important gem-difluoromethylene-linked twin molecules. The unique π-conjugated aryl-fused 1,3-azolic moiety in difluoromethyl bromide substrates could stabilise the reaction intermediates, which promotes the reactivities, providing facile access to the cross-coupling products in good to excellent yields, and allowing significant functional group tolerance. The reaction exhibits an enhanced neighbouring-group-participation effect. This method could provide a new strategy for the construction of gem-difluoromethylene-linked identical or nonidentical twin drugs through further functionalisation of 1,3-azolic skeletons.

Synthesis and anti-hypertensive effects of the twin drug of nicotinic acid and quercetin tetramethyl ether.

A novel twin drug consisting of nicotinic acid (VB3) and quercetin tetramethyl ether (QTME) has been synthesized as an antihypertensive in a total yield of 79.2% through methylation, hydrolysis, acylation and esterification starting from rutin. The structures of synthesized compounds were elucidated by 1H-NMR, 13C-NMR and elemental analysis. The anti-hypertensive effects of an oral daily dose (15 mg/kg) of the synthesized compounds in spontaneously hypertensive (SHR) rats and normotensive Wistar Kyoto (WKY) rats were analysed. The data demonstrate that the twin drug VB3-QTME both reduces the elevated blood pressure and prolongs the action time in SHR rats without effect on WKY rats. However, definitive evidence of a precise mechanism of action by which VB3-QTME might decrease blood pressure remains elusive. Based on the results, the therapeutic potential of this twin drug is discussed.

3,5-Dimethoxy-4-(3-(2-carbonyl-ethyldisulfanyl)-propionyl)-benzoic acid 4-guanidino-butyl ester: A novel twin drug that prevents primary cardiac myocytes from hypoxia-induced apoptosis

Leonurine possesses cardioprotective effects in myocardial ischemia due to its anti-apoptotic properties. However, the process to isolate and purify leonurine is difficult, because of its low content in the Herb Leonuri and its impurity. Moreover, the high dosage used indicates low potency of leonurine. To overcome these defects, we had synthesized a novel twin drug of leonurine, 3,5-dimethoxy-4-(3-(2-carbonyl-ethyldisulfanyl)-propionyl)-benzoic acid 4-guanidino-butyl ester (compound 2). In this paper, we focused on investigating the cardioprotective effect and underlying mechanisms of compound 2. Our data showed that cell viability was significantly increased in a dose-dependent manner and the levels of lactate dehydrogenase (LDH) and creatine kinase (CK) were also significantly attenuated in the compound 2-treated group. In addition, we observed the cardioprotective effects by Hoechst 33258 nucleus staining, JC-1 staining, Annexin V-FITC/PI staining and transmission electron microscopy. Compound 2 inhibited apoptosis by reducing the ratio of Bcl-2/Bax, decreasing cleaved-caspase-3 expression and enhancing the phosphorylation of Akt. Furthermore, the phosphorylation effect of compound 2 was reversed by LY294002 the phosphatidylinositol-3-kinase (PI3K) inhibitor from happening. We concluded that compound 2 played a cardioprotective role in hypoxia-induced primary cardiac myocytes apoptosis partly via modulating the PI3K/Akt pathway at a 10-fold lower concentration than leonurine.

Synthesis and biological evaluation of primaquine–chloroquine twin drug: a novel heme-interacting molecule prevents free heme and hydroxyl radical-mediated protein degradation

Accumulations of oxidized and degraded proteins are the markers for oxidative stress. Degradation of hemoprotein e.g. hemoglobin during different pathological conditions produces heme, which induces oxidative stress and inflammation through its pro-oxidant nature and leads to protein degradation. Moreover reduced transition-metal ions Fe2+ can generate toxic hydroxyl radicals (˙OH) and leads to protein degradation. Therefore, synthesis of a compound that will detoxify free heme, chelate Fe+2 and show antioxidant activity by scavenging ˙OH would be beneficial against protein degradation. Here, we report the synthesis of a novel heme-interacting primaquine–chloroquine twin drug (PQCL) that could chelate free iron and showed excellent antioxidant activity as evident from ferric reducing antioxidant power. PQCL prevented ˙OH and heme-mediated protein degradation. PQCL also could scavenge nitrogen-centered free radical (2,2-diphenyl-1-picrylhydrazyl). Thus, we have synthesized PQCL, a heme-interacting molecule, which is capable to prevent free heme and ˙OH-mediated protein degradation.

The twin drug approach for novel nicotinic acetylcholine receptor (nAChR) ligands: Synthesis and structure–affinity relationships

The twin drug approach for novel nicotinic acetylcholine receptor (nAChR) ligands: Synthesis and structure–affinity relationships

Synthesis and Biological Activities of Some N-Acyl-2,6-diaminopyridines and Related Linker Mode Identical Twin Drugs

Synthesis and Biological Activities of Some N-Acyl-2,6-diaminopyridines and Related Linker Mode Identical Twin Drugs

Primaquine-NSAID twin drugs: Synthesis, radical scavenging, antioxidant and Fe2+ chelating activity

Novel primaquine conjugates with non-steroidal anti-inlammatory drugs (PQ-NSAIDs, 4a-h) were prepared, fully chemically characterized and screened for radical scavenging and antioxidant activities. The synthetic procedure leading to twin drugs 4a-h involved two steps: i) preparation of NSAID benzotriazolides 3a-h from the corresponding NSAID (ibuprofen, ketoprofen, fenoprofen, ketoprofen hydroxy and methylene analogues, diclofenac or indomethacin) and benzotriazole carboxylic acid chloride (BtCOCl, 1), ii) reaction of intermediates 3a-h with PQ. The prepared PQ-NSAIDs exerted moderate activities in the DPPH free radical test and β-carotene-linoleic acid assay. Moreover, ketoprofen derivatives 4d and 4b demonstrated a notable Fe2+ chelating ability as well. On the other hand, negligible antiproliferative and antituberculotic effects of conjugates 4a-h were observed.

Urea and carbamate derivatives of primaquine: Synthesis, cytostatic and antioxidant activities

The novel urea primaquine derivatives 3 were prepared by aminolysis of primaquine benzotriazolide 2 with several hydroxyamines and ethylendiamine, while carbamates 4 were synthesized from the same precursor 2 and alcohols. All compounds are fully chemically characterized and evaluated for their cytostatic and antioxidant activities. The most prominent antiproliferative activity was obtained by compounds 3c, 3d, 3g, and 5b (IC 50 = 9–40 μM). 1-(5-Hydroxypentyl)-3-[4-(6-methoxy-quinolin-8-ylamino)-pentyl]urea ( 3c) showed extreme selectivity toward SW 620 colon cancer cells (IC 50 = 0.2 μM) and a bit less toward lung cancer cells H 460. Hydroxyurea 3h showed the highest interaction with DPPH. Primaquine twin drug 3g showed very significant inhibition on LOX soybean (IC 50 = 62 μM). Almost all the tested derivatives highly inhibited lipid peroxidation, significantly stronger than primaquine phosphate.

Amoxicillin and amoxicillin plus clavulanate: a safety review

Despite the considerable number of newer antibacterials made available over the past decades, amoxicillin, alone or in combination with clavulanic acid, still accounts among the most widely used antibacterial agents. Although they are often considered ‘twin drugs’, they are different both in terms of antibacterial activities and of safety profile. It is well documented that the clavulanate component may cause adverse reactions by itself, thus exposing patients to further, and sometimes undue, risks. Although amoxicillin/clavulanate should be considered as an alternative agent only for the treatment of resistant bacteria, evidence shows that it is often used also when a narrow-spectrum antibiotic would have been just as effective. This prescription habit may have serious consequences in terms of patients' safety, as well as in terms of the development of bacterial resistance.

Synthesis of novel twin drug consisting of 8-oxaendoethanotetrahydromorphides with a 1,4-dioxane spacer and its pharmacological activities: μ, κ, and putative ε opioid receptor antagonists

A twin drug consisting of 8-oxaendoethanotetrahydromorphides with a 1,4-dioxane spacer, NS29, was synthesized from a naltrexone derivative. The structure of compound 8, the precursor of NS29, was determined by X-ray crystallography. Monomeric NS28 showed μ opioid receptor antagonist activity, whereas dimeric NS29, consisting of two NS28 units, showed antagonist activities for μ, κ, and the putative ε opioid receptor agonists. Twin drug NS29 and its derivatives are expected to be unique pharmacological tools for investigation of opioid receptor types

Two Identical Twin Nitrogen Mustard Agents that Express Rapid Alkylation Activity at Physiological pH 7.4 and 37°C

Two nitrogen mustard (N-mustard ) agents were synthesized utilizing ethylene diamine and hexane diamine as the parent compounds. These N-mustard agents were solids at 25 o C and stable while stored dry at -10 o C. The two N-mustards assumed the configuration of identical twin drugs which when placed in aqueous solution were highly reactive. Both N-mustards were soluble in aqueous NaHCO3 buffer and expressed alkylation activity directed towards a nucleophilic primary amine target (4-chloroaniline) at blood pH 7.4 and 37 o C. Utilizing the fluorescent probe fluorescamine, which is highly specific for primary amines, the quantity of unreacted nucleophilic 4-chloroaniline remaining after a known time period was determined. This enabled the calculation of rate constants and the determination of rate equation for alkylation to be first-order for N,N,N',N'-tetrakis(2-chloroethyl)ethane-1,2-diamine and zero-order for N,N,N',N'- tetrakis(2-chloroethyl)hexane-1,6-diamine. Molecular property descriptors such as Log P, parachor, molar volume, molar refractivity, dipole, molecular volume & area, and polar surface area were calculated for comparison. Zero violations of the Rule of 5 indicates these two mustard agents will have good bioavailability and good bioactivity.