Antitumor activity of semisynthetic derivatives of Aconitum alkaloids.

We recently synthesized from aconitine a series of drugs with in vitro and in vivo antitumor properties, among which bis[O-(14-benzoylaconine-8-yl)]suberate (BBAS) was the most active (Eur J Med Chem 2012; 54: 343). In the present work, we used the NCI panel of 60 human tumor cell lines to identify the most sensitive cell lines and drugs with comparable cytotoxicity profiles. GI50 values of BBAS ranged between 0.12 and 6.5 µM. Activity was higher than average for leukemia and melanoma cell lines, especially SK-MEL-5 and SK-MEL-28, for the COLO-205 and HT-29 (colorectal) and MDA-MB-468 (breast) cancer cell lines. We evaluated the correlation between the GI50 of BBAS and those of 125 antiproliferative compounds with various mechanisms of action, using Bonferroni correction for multiple testing, and we observed a highly significant correlation with the GI50s of nitrosoureas. Interestingly, BBAS cytotoxicity was inversely correlated with the expression levels of MGMT (p = 0.009), an enzyme involved in the repair of nitrosourea-induced DNA damage. However, no correlation was found with the expression of 102 other genes involved in DNA repair. Antitumor activity was tested on immunodeficient mice with subcutaneously xenografted COLO-205, HT-29, MDA-MB-468, SK-MEL-5 and SK-MEL-28 cell lines. At 10 mg/kg, there was a significant reduction in tumor size with T/C values of 41 % and 43 % for COLO-205 and SK-MEL-28 cell lines, respectively. The drug was less active on HT-29 and SK-MEL-5 and inactive on MDA-MB-468 xenografts. Cell cycle studies showed an accumulation of BBAS-treated cells in G2/M phase after treatment at 20 µM. Together, our results allowed the identification of a potentially new class of anticancer agent displaying a mechanism of action related to that of nitrosoureas.

Hemisynthesis and antiproliferative properties of mono-[O-(14-benzoylaconine-8-yl)]esters and bis-[O-(14-benzoylaconine-8-yl)]esters.

A series of mono- and bifunctional acyl compounds, build from the 8-O-azeloyl-14-benzoylaconine scaffold and differing by the length of the alkyl linker chain, were synthesised and evaluated against a panel of human tumour cell lines, A-549 (lung cancer), MCF-7 (breast cancer) and HCT-15 (colon cancer). None of the mono-[O-(14-benzoylaconine-8-yl)]esters displayed in vitro activity against tumour cells (IC(50) > 60 µM). However, three bis-[O-(14-benzoylaconine-8-yl)]esters presented a noticeable in vitro cytotoxic activity, those bearing 7, 8 and 9 carbon atoms between the two aconitine moieties, with IC(50)s ranging between 4 and 28 µM. The most active, bis[O-(14-benzoylaconine-8-yl)]suberate, was then evaluated in vivo in immunodeficient mice bearing human tumour xenografts originating from MCF-7 and HCT-15 cells. For MCF-7 cells, administration of five doses every 4 days, and weekly administration of 4 doses resulted in T/C percent values of 36% (p = 0.001) and 56% (p = 0.02) on day 45, respectively. For HCT-15 cells, administration of five doses every 3 days resulted in 49% tumour regression on the 25th day (p = 0.00001).

Synthesis and in vitro cytostatic activity of new beta-D-arabino furan[1',2':4,5]oxazolo- and arabino-pyrimidinone derivatives.

A series of nucleoside derivatives was obtained via heteroatom annulation of the amino oxazoline of D-(-)-arabinose. Unequivocal proofs for the stereostructure of some new arabinosyl pyrimidinone derivatives were obtained by X-ray structure analysis. These newly synthesized compounds were then evaluated for their cytostatic activity against murine leukemia (L1210), and human T-lymphocytes (Molt 4/C8 and CEM). Of all the compounds in the series, the protected silylated tricyclic fused pyrimidinone 10 showed the most significant antitumor activity against murine leukemia L1210 (IC(50)=6 microM), and human T-lymphocytes cells Molt 4/C8 (IC(50)=7.9 microM) and CEM/0 cell lines (IC(50)=7.5 microM). None of the compounds exhibited significant antiviral inhibitory activities.

Synthesis and preliminary evaluation of new 1- and 3-[1-(2-hydroxy-3-phenoxypropyl)]xanthines from 2-amino-2-oxazolines as potential A1 and A2A adenosine receptor antagonists.

The development of potent and selective adenosine receptor ligands as potential drugs is an active area of research. Xanthines are one of the most important classes of adenosine receptor antagonists and have been widely developed in terms of affinity and selectivity for adenosine receptors. We recently developed new original pathways for the synthesis of xanthine analogues starting from 5-substituted-2-amino-2-oxazoline 5 as a synthon. These procedures allowed us to selectively introduce a large, functionalized and beta-adrenergic 2-hydroxy-3-phenoxypropyl pharmacophore at the 1- and 3-position of the xanthine moiety which allowed further structural modifications. In this study, we present a new synthetic access to racemic xanthine derivatives 1-4 from 5, and their evaluation as adenosine A1, A2A and A3 receptor ligands in radioligand binding studies. The 2-hydroxy-3-phenoxypropyl moiety was well tolerated in the 3-position of the xanthine core, while its introduction in the 1-position of the xanthine moiety led to a large decrease in adenosine receptor affinity. 1,7-Dimethyl-3-[1-(2-chloro-3-phenoxypropyl)]-8-(3,4,5-trimethoxystyryl)xanthine (2n) was the most potent and selective A2A antagonist of the present series (Ki=44 nM, >>200-fold selective vs A1). 1-Propyl-3-[1-(2-hydroxy-3-phenoxypropyl)]-8-noradamantylxanthine (3f) was identified as a potent (KiA1=21 nM) and highly selective (>>350-fold vs A2A and A3 receptor) adenosine A1 receptor antagonist.

8-O-Azeloyl-14-benzoylaconine: a new alkaloid from the roots of Aconitum karacolicum Rapcs and its antiproliferative activities.

A new alkaloid of Aconitum karacolicum Rapcs, from the Ranunculaceae family, collected in Kirghizstan, was isolated from the roots of this plant, using a purification scheme based upon its in vitro antiproliferative properties against three human tumour cell lines in culture. Structural identification was performed using high resolution MS-MS mass spectrometry and (1)H, (13)C, 2D NOESY NMR spectroscopy analysis. This compound consists of a 14-benzoylaconine moiety substituted on C-8 by an azeloyl chain. It presents in vitro cytotoxicity with an IC(50) of about 10-20 microM, which warrants further investigation on its possible interest in cancer chemotherapy.

Derivatization of (+/-)-5-[(2-methylphenoxy)methyl]-2-amino-2-oxazoline, an imidazoline binding sites ligand, with (+)-(R)-alpha-methylbenzyl isocyanate for drug monitoring purposes.

The derivatization of racemic 5-[(2-methylphenoxy)methyl]-2-amino-2-oxazoline, developed as an imidazoline binding sites ligand, with (+)-(R)-alpha-methylbenzyl isocyanate was performed in chloroform. The reaction led to two pairs of diastereomers, which were separated by RP-HPLC. A kinetic study of the derivatization reaction was achieved in order to establish conditions suitable for experimental drug monitoring.