The concept of antiaromaticity as applied to 4n-x electron monocyclic conjugated systems is examined and two subtypes distinguished. Relative antiaromaticity is the term which describes cyclic systems which are less stable than acyclic conjugated analogues. Absolute antiaromaticity refers to cyclic systems which are less stable than even nonconjugated models (e.g., ethylene). The extensive experimental evidence for absolute antiaromaticity (particularly for cyclobutadiene and cyclopropenide) is critically examined and judged inconclusive in view of the existence of alternate, plausible rationalizations. Theoretical analysis also challenges the reality of absolute antiaromaticity, at least in the monocyclic series. Relative antiaromaticity is affirmed, but only for the three smallest monocyclic systems (the two mentioned above plus cyclopentadienylium).Previous to 1965, nonaromatic cyclic conjugated systems had sometimes been termed "pseudoaromatic". Included in this category, of course, were molecules having monocyclic systems of 4n-x electrons. In 1965 Breslow concluded that certain 4n monocycles are actually "antiaromatic", these including at least cyclopropenide (C3-) and 1,3-cyclobutadiene (C4), as well as possibly cyclopentadienylium (C5+).1 The term "antiaromatic" denoted and emphasized destabilizing cyclic conjugation. Two reference systems were considered for more
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.
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