Synthesis and Characterization of the Antitumor Activities of Analogues of Meridine, a Marine Pyridoacridine Alkaloid

Abstract

Marine compounds with pyridoacridine skeletons are known to exhibit interesting antitumor activities. Among these compounds, meridine has already been reported as having significant antitumor activities in vitro. We synthesized 24 analogues of meridine substituted on ring A with the aim of obtaining compounds that display significantly higher in vitro antitumor activities than meridine. The 24 compounds and meridine used as a control compound were tested at 6 different concentrations on 12 different human cancer cell lines including various histopathological types (glioblastomas and breast, colon, lung, prostate, and bladder cancers). The IC(50) value (i.e., the drug concentration inhibiting the mean growth value of the 12 cell lines by 50%) of these 25 compounds ranged over 5 log concentrations, i.e., between 10 and 0.0001 microM, with four of the compounds exhibiting a significantly higher in vitro antitumor activity than meridine. These compounds will now be subjected to further pharmacological investigation including in vivo testing on both conventional murine tumors and human tumors grafted onto nude mice.

Marine pyridoacridine alkaloids and synthetic analogues as antitumor agents

“…5). For our part, we focused the structure modulation of meridine on cycle A and, involving a similar pathway, we were interested in compounds 58-60 29 , of which some of them have been previously described as synthetic intermediates in the synthesis of meridine by Kitahara et al 25 , (Fig. 6 and Table I).…”

“…Our compounds were tested on 12 different human cancer cell lines including three glioblastomas (A-172, U-373 MG, and U-87 MG), two colon (HCT-15 and LoVo), two non-small-cell-lung (A-549 and A-427), two bladder (J-82 and T-24), one prostate (PC-3) and two breast (T-47D and MCF-7) cancer models 29 (Table III). The cytotoxicity of nitro-derivatives is lower related to trifluoroacetamido-intermediates which are equivalent to the corresponding pentacyclic compounds.…”

Platinated Copper(3‐Clip‐Phen) Complexes as Effective DNA‐Cleaving and Cytotoxic Agents

“…In the present study, we report on the fact that platinated Cu(3-Clip-Phen) complexes with weak cytotoxic activity in vitro (as revealed by the MTT colorimetric assay) [34][35][36] are associated with marked antimigratory effects (as revealed by computer-assisted phase-contrast microscopy), [37][38][39] and vice versa.…”

Enantioselective Synthesis of Clavepictine Analogues and Evaluation of Their Cytotoxic Activity

“…[4] We made use of the colourimetric MTT assay, which indirectly assesses the effect of potential anticancer compounds on the overall growth of adherent cell lines. [16,17] The percentages of tumor cells surviving in each experimental conditions were determined after four days of culture in the presence (or absence, i.e., control) of the drugs (see Table 1). The percentages of cells of each of the six cancer models present in the control were normalised arbitrarily at 100%.…”

“…This process was carried out by means of the colourimetric MTT assay, as detailed previously. [16,17] This assessment of cell population growth is based on the capability of living cells to reduce the yellow product MTT [3-(4,5)-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; Sigma, St Louis, MO] to a blue product, formazan, 2070 by a reduction reaction occurring in the mitochondria. The number of living cells is directly proportional to the intensity of the blue colour, which is quantitatively measured by spectrophotometry on a DIAS microplate reader (Dynatech Laboratories, Guyancourt, France) at a 570 nm wavelength (with a reference of 630 nm).…”