5-N-Acetylardeemin, a novel heterocyclic compound which reverses multiple drug resistance in tumor cells. I. Taxonomy and fermentation of the producing organism and biological activity.

Abstract

The ardeemins are a new family of secondary metabolites produced by submerged fermentation of a fungus which was isolated from a soil sample collected in Brazil. Based on taxonomic studies, the producing culture was identified as Aspergillus fischeri var. brasiliensis strain AB 1826M-35. 5-7V-Acetylardeemin potentiated the cytotoxicity of the anticancer agent vinblastine in multidrug resistant humantumorcells.Multidrug resistance (MDR)is characterized by the development of resistance to several structurally unrelated anticancer agents and is a major cause of failure of cancer chemotherapy. The appearance of a specific glycoprotein, P-170, is generally associated with resistant cells1*. P-170 is a membrane associated glycoprotein thought to actively export cytotoxic compoundssuch as anthracyclines and Vinca alkaloids from resistant tumor cells2). Although several compoundsare knownto reverse MDR, none are used clinically because of adverse side effects3*. In the course of screening for modulators of MDR, we discovered a family of novel compounds which we have called ardeemins. 5-JV-Acetylardeemin appears to be the most efficacious of these compoundsin the reversal of MDR. The compoundsare produced in the fermentation broth of Aspergillus fischeri var. brasiliensis strain AB 1826M-35. This paper describes the taxonomy and the fermentation of the producing microorganism and the biological activity of ardeemin and 5-7V-acetylardeemin. The isolation and structural elucidation of these and other congeners are described in an accompanying publication4*. Materials and Methods MicroorganismsStrain AB1826M-35 was isolated from soil collected in Brazil. A subculture of the microorganism was deposited at

MDR Reversal by Deprenylated Tetracyclic and Hexacyclic Analogues of N-Acetylardeemin: Confirmation of the Ardeemin Pharmacophore

“…C-ring rigidification by unsaturation did not lead to increased activity (compound 5h), even though it was accompanied by an increase in lipophilicity due to the introduction of a bromine substituent, which is very often accompanied by an increase MDR in reversal actvity [1]. A similar increase in lipophilicity associated with the introduction of a prenyl substituent in compound 5i actually decreased its activity compared with that of 5 e , which has a similar stereochemistry, although this was probably associated with the lack of the N-acetyl group, which seems to be important for the activity of N-acetylardeemin [3]. Similarly, the lipophilic seco analogue 6, lacking a N-acetyl group, was inactive.…”

“…brasiliensis, which has a very potent MDR reverser activity (IC 50 = 5-30 µM) and low toxicity. This compound is able to potentiate the cytotoxicity of vinblastine, doxorubicin or paclitaxel in multidrug resistant human tumour cells with 10-fold potency with respect to verapamil, the standard anti-MDR drug [3]. Its glycine analogue (1b) and its trifluoro derivative are also potent Fig.…”

“…For this reason, this compound was submitted to further studies regarding its chemosensitising activity, starting with a direct comparison of the activity of 5b and verapamil by incubation of both compounds with Schabel cells in the presence of several concentrations of doxorubicin ranging from 0.02 µM to 5 µM, which allowed to construct a drug dose-cell response curve for each compound. A direct comparison with Nacetylardeemin was not possible due to lack of material, but this compound has been previously shown [3,17] to have an MDR reversal potency about 10-fold that of verapamil, thus providing a basis for comparison. As shown in Fig.…”

Syntheses of Quinazoline-2,4-dione Alkaloids and Analogues from Mexican Zanthoxylum Species †

“…Quinazolinone and quinazolinedione derivatives are of considerable interest because of their wide array of pharmacological properties [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15]. We have been specifically interested in the synthesis of novel heterocycles containing the quinazoline-2,4-dione backbone, which are known to exhibit potential anti-hypertensive properties [16][17][18][19][20].…”

Enantioselective organocatalytic construction of pyrroloindolines by a cascade addition–cyclization strategy: Synthesis of (–)-flustramine B

“…Furthermore, McAlpine and coworkers (7)(8)(9) have reported that the pyrroloindoline 5-N-acetylardeemin demonstrates the ability to restore vinblastine sensitivity to tumor cell lines that manifest ''operational resistance'' to cytotoxic agents. The hydroxypyrroloindoline gypsetin has evoked interest as a potential inhibitor of the enzyme acyl-CoA:cholesterol acyltransferase and as such might find therapeutic use as a cholesterol-lowering agent (10)(11)(12).…”