HIV-1 neutralization and tumor cell proliferation inhibition in vitro by simplified analogs of pyrido[4,3,2-mn]thiazolo[5,4-b]acridine marine alkaloids

Abstract

The antiviral/antitumor marine alkaloid dercitin was used as a lead compound to design analogues with anti-HIV and tumor inhibitory activities. Deletion of structural features contributing to cytotoxicity led to analogues with lowered T-lymphocyte toxicity profiles. One compound, 5, induced complete protection against HIV-1 infectivity in vitro at 12.5 micrograms/mL (38 microM) without T-cell toxicity up to 400 micrograms/mL. Compound 4 and 5 also inhibited the binding of HIV-1 to H-9 lymphocytes. These compounds may exert antiviral activity by a unique dual extracellular and intracellular mode of action--both preventing viral attachment to lymphocytes as well as intercalating with viral nucleic acid. Analogues with higher cytotoxicity such as 2 which retain the thiazole ring of the natural product proved effective in completely inhibiting the cell proliferation of breast, colon, and lung tumor cell lines at 1.5 microM concentration compared to a 70 microM dose level of 5-fluorouracil. A means of molecular separation of antiviral activity from cytotoxicity was thus achieved, and putative pharmacophores for antiviral and antitumor actions of the prototype molecule dercitin have been deduced. The 2-thio-9-acridinone derivatives 4 and 5 represent a new structural type exhibiting activity against HIV in vitro, serving as chemical leads in the design of anti-AIDS agents, while thiazolo[5,4-b]acridines such as 2 provide leads in the drug design of new antitumor agents.

A mini review on pyridoacridines: Prospective lead compounds in medicinal chemistry

“…The presence of a sulphur atom seemed to be essential for antiviral activity of dercitin analogues while the acidic carboxylic group decreases viral affinity towards lymphocytes. Similarly, the occurrence of a mercaptoacetic acid group at the C-2 position in compounds 18 and 19 on the tricyclic ABC acridine nucleus demonstrated highest HIV-1 neutralization activity along with the partial inhibition of viral affinity towards lymphocytes [48] .…”

Bioactive Marine Alkaloids

“…Almost all known pyridoacridine alkaloids are reported to have significant cytotoxicity. The compounds of this group also display several specific biological properties, such as inhibition to topoisomerase II, [12][13][14] antiHIV activity, 15 Ca 2+ release activity, 16 metal chelating properties 17 and intercalation of DNA 17 property.…”

“…The iminoquinone system in ( 2) is readily reduced in the ionization stage of a mass spectrometer, (M+2 ion in EIMS, MH+2 for FABMS), a typical for quinones. The vivid purple-colored ascidian Lissoclinum vareau 25 from Fiji has furnished two bright crimson pigments varamine-A ( 16) and varamine-B (17) which occurs with antitumor alkaloid, varacin (15). 26 Varamine-A ( 16) and varamine-B (17) have a parent tetracyclic aromatic ring system at the same oxidation level as the systodytin-A methylation product (14).…”

Boron trifluoride etherate promoted microwave-assisted synthesis of antimalarial acridones

“…1) are of worldwide interest because of their wide range of biological properties, including antitumor, anticancer, antimalarial, anti-HIV, antiviral, and antifungal activities. [1][2][3][4][5][6][7][8][9][10][11][12][13] The intriguing structural features and therapeutic importance of acridone scaffold has attracted the great attention of organic and medicinal chemists to discover new synthetic routes [14][15][16][17][18] for the generation of novel acridones to be evaluated for biological activities and structure-activity relationships (SAR).…”