Curative properties of noninternalizing antibody-drug conjugates based on maytansinoids.

It is generally thought that the anticancer efficacy of antibody-drug conjugates (ADC) relies on their internalization by cancer cells. However, recent work on an ADC that targets fibronectin in the tumor microenvironment suggests this may not be necessary. The alternatively spliced extra domains A and B (EDA and EDB) of fibronectin offer appealing targets for ADC development, because the antigen is strongly expressed in many solid human tumors and nearly undetectable in normal tissues except for the female reproductive system. In this study, we describe the properties of a set of ADCs based on an antibody targeting the alternatively spliced EDA of fibronectin coupled to one of a set of potent cytotoxic drugs (DM1 or one of two duocarmycin derivatives). The DM1 conjugate SIP(F8)-SS-DM1 mediated potent antitumor activity in mice bearing DM1-sensitive F9 tumors but not DM1-insensitive CT26 tumors. Quantitative biodistribution studies and microscopic analyses confirmed a preferential accumulation of SIP(F8)-SS-DM1 in the subendothelial extracellular matrix of tumors, similar to the pattern observed for unmodified antibody. Notably, we found that treatments were well tolerated at efficacious doses that were fully curative and compatible with pharmaceutical development. Our findings offer a preclinical proof-of-concept for curative ADC targeting the tumor microenvironment that do not rely upon antigen internalization.

New aryldithiolethione derivatives as potent histone deacetylase inhibitors.

A series of dithiolethione derivatives was synthesized and the in vitro HDAC inhibitory activity was tested. The most active compounds, 1 and 2, exhibited an IC(50) in nM range with a strong hyperacetylation of histone H4 in A549 cells. The HDAC inhibitory activity comparable to that of SAHA and the inhibition of A549 cell proliferation suggest that these compounds are worthy of further studies as potential anticancer agents.

HPLC determination of novel dithiolethione containing drugs and its application for in vivo studies in rats.

A panel of new drugs obtained by grafting a sulfurated moiety, i.e. 5-(4-hydroxyphenyl)-3H-1,2-dithiole-3-thione (ADTOH) onto existing drugs have been synthesized and their in vivo action is under preclinical evaluation. In the present paper we describe rapid HPLC methods to detect ADTOH derivatives of valproic acid (ACS2), sildenafil (ACS6), aspirin (ACS14) and diclofenac (ACS15) in plasma. These methods allow the simultaneous detection of the potential drugs and of ADTOH moiety. In the case of ACS14 the de-acetylated metabolite (ACS21) can also be concomitantly measured. The chromatographic separation was performed on a C18 column, applying a mobile phase consisting of a mixture of trifluoroacetic acid and acetonitrile. ADTOH, ACS6, ACS14, ACS21 were separated isocratically whereas ACS2 and ACS15 were separated applying gradient elution. The methods are precise and accurate, with a low quantification limit of 200 nM for ACS2, ACS15 and ACS21 or 100 nM for ADTOH, ACS6 and ACS14. The mean absolute recovery for all tested molecules was always found to be close to 100%. The methods are shown to be selective and linear in the range 0.2-50 microM and thus appear suitable for pharmacokinetic studies with ADTOH containing compounds, as indicated by exemplificative experiments performed with intravenous administration of the drugs to rats.

New prostaglandin derivative for glaucoma treatment.

A hydrogen sulphide-releasing derivative of latanoprost acid (ACS 67) was synthesized and tested in vivo to evaluate its activity on reduction of intraocular pressure and tolerability. Glutathione (GSH) and cGMP content were also measured in the aqueous humour. The increased reduction of intraocular pressure, with a marked increase of GSH and cGMP and the related potential neuroprotective properties, make this compound interesting for the treatment of glaucoma. This is the first time that an application of a hydrogen sulphide-releasing molecule is reported for the treatment of ocular diseases.

Pharmacological profile of a novel H(2)S-releasing aspirin.

The pharmacological profile of a new, safe, and effective hydrogen sulfide (H(2)S)-releasing derivative of aspirin (ACS14) is described. We report the synthesis of ACS14, and of its deacetylated metabolite (ACS21), the preliminary pharmacokinetics, and its in vivo metabolism, with the H(2)S plasma levels after intravenous administration in the rat. ACS14 maintains the thromboxane-suppressing activity of the parent compound, but seems to spare the gastric mucosa, by affecting redox imbalance through increased H(2)S/glutathione formation, heme oxygenase-1 promoter activity, and isoprostane suppression.

New sulfurated derivatives of valproic acid with enhanced histone deacetylase inhibitory activity.

One dithiolthione and two new methanethiosulfonate derivatives of valproic acid (VPA) were synthesized and tested in vitro as histone deacetylase (HDAC) inhibitors. The new molecules, as well as their sulfurated moieties, exhibited a much stronger inhibition of HDAC enzymatic and antiproliferative activities and histone hyperacetylation than VPA. ACS 2 is the most interesting compound among the new VPA derivatives and its sulfurated moiety, 5-(4-hydroxyphenyl)-3H-1,2-dithiole-3-thione, also known to be a metabolite of anethole trithione, seems to contribute significantly to its activity. This is the first time that HDAC inhibitory activity is described for dithiolethiones and thiosulfonates.

[4-(2H-1,2,3-benzotriazol-2-yl)phenoxy]alkanoic acids as agonists of peroxisome proliferator-activated receptors (PPARs).

A series of [4-(2H-1,2,3-benzotriazol-2-yl)phenoxy]alkanoic acids has been synthesized and tested as agonists of Peroxisome Proliferator-Activated Receptor (PPAR) alpha, gamma, and delta. Three compounds displayed 56 to 96% of maximal activity of the reference drug Wy-14643 on PPARalpha, and two of these, i.e., 1 and 5, exhibited also moderate activity on either PPARgamma or delta with efficacy equal to 50% and 46% of that of rosiglitazone and GW 501516, respectively. Thus, compounds 1 and 5 represent interesting starting point for preparing novel agents for the treatment of dyslipidemia or of dyslipidemic type-2 diabetes.