Alteration of lipophilicity of aromatic cationic antitumour drugs greatly affects cellular uptake and binding to plasma proteins. Changes in lipophilicity also affect host toxicity, and optimal lipophilicity may be a critical factor in the design of analogues with high antitumour activity.

A series of compounds related to the nonnucleoside reverse transcriptase (RT) inhibitor (NNRTI) oxathiin carboxanilide (UC84) were evaluated for activity against the human immunodeficiency virus (HIV) to determine structural requirements for anti-HIV activity. Twenty-seven compounds representative of the more than 400 Uniroyal Chemical Company (UC) compounds were evaluated for structure-activity relationships. Several of the compounds evaluated were highly active, with 50% effective concentrations in the nanomolar range and therapeutic indices of >1,000. Highly synergistic anti-HIV activity was observed for each compound when used in combination with 3-azido-3-deoxythymidine; additive to slightly synergistic interactions were observed with the compounds used in combination with dideoxycytidine. In combination with the NNRTI costatolide, only UC38 synergistically inhibited HIV type 1. Residues in the RT which, when mutated, impart resistance to the carboxanilide compounds were defined by evaluation of the UC compounds against a panel of NNRTI-resistant virus isolates selected in cell culture, against virus variants with site-directed mutations, and against RTs containing defined single amino acid changes. The mutations included changes in RT amino acids 100, 101, 103, 106, 108, and 181. The results with isolates selected in cell culture indicate that the carboxanilide compounds interact with the RT at two vulnerable sites, selecting UC-resistant virus isolates with the Y-to-C mutation at position 181 (Y181C) or the L100I substitution. A resistant virus isolate containing both Y181C and K101E amino acid changes and another with both Y181C and V106A mutations were isolated. In combination with calanolide A, an NNRTI which retains activity against virus isolates with the single Y181C mutation, UC10 rapidly selected a virus isolate with the K103N mutation. The merits of selecting potential candidate anti-HIV agents to be used in rational combination drug design as part of an armamentarium of highly active anti-HIV compounds are discussed.

To better understand V gene usage, specificity, and clonal origins of IgE Abs in allergic reactions, we have constructed a combinatorial Ab library from the mRNA of an adult patient with atopic dermatitis. Sequence analysis of random clones revealed that 33% of clones used the IGHV6-1 H chain V gene segment, the only member of the VH6 gene family. IGHV6-1 is rarely used in the expressed adult repertoire; however, it is associated with fetal derived Abs. Features of the VH6 rearrangements included short complementarity-determining region 3, frequent use of IGHD7-27 D gene, and little nucleotide addition at the D-J junction. There was also a low level of mutation compared with VH1, VH3, and VH4 rearrangements. The library was expressed as phage-Fab fusions, and specific phage selected by panning on the egg allergen ovomucoid. Upon expression as soluble IgE Fabs, 12 clones demonstrated binding to ovomucoid, skim milk, and BSA by ELISA. Nucleotide sequencing demonstrated that the IGHV6-1 V gene segment encoded each of the 12 multiply reactive IgE Fabs. A cyclic peptide was designed from the complementarity-determining region 3 of several of these clones. The cyclic peptide bound both self and nonself Ags, including ovomucoid, human IgG, tetanus toxoid, and human and bovine von Willebrand factor. These results suggest that some IgE Abs may bind more than one Ag, which would have important implications for understanding the multiple sensitivities seen in conditions such as atopic dermatitis.

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A large variety of carboxanilide and thiocarboxanilide derivatives in which the original oxathiin or aliphatic moieties present in the prototype compounds UC84 and UC38 were replaced by an (un) substituted furanyl, thienyl, phenyl, or pyrrole entity have been evaluated for activity against wild-type human immunodeficiency virus type 1 strain IIIB [HIV-1 (IIIB)] and a series of mutant virus strains derived thereof. The mutant viruses contained either the Leu-100-->Ile, Lys-103-->Asn, Val-106-->Ala, Glu-138-->Lys, Tyr-181-->Cys, or Tyr-188-->Leu mutation in their reverse transcriptase. Several 3-(2-methylfuranyl)- and 3-(2-methylthienyl)-thiocarboxanilide ester, (thio)ether, and oxime ether derivatives showed exquisitely potent antiviral activity against wild-type HIV-1 (50% effective concentration, 0.009 to 0.021 microM). The pentenylethers of the 2-methylfuranyl and 2-methylthienyl derivatives (i.e., 313, N-[4-chloro-3-(3-methyl-2-butenyloxy)phenyl]- 2-methyl-3-furancarbothioamide or UC-781, and 314, N-[4-chloro-3-(3-methyl-2-butenyloxy)phenyl] -2-methyl-3-thiophenecarbothioamide or UC-82) proved virtually equally inhibitory for wild-type and the Ile-100, Ala-106, and Lys-138 mutant virus strains (50% effective concentration, 0.015 to 0.021 microM). Their inhibitory effect against the Asn-103 and Cys-181 reverse transcriptase mutant virus strains was decreased only four- to sevenfold compared with wildtype virus. UC-781 and UC-82 should be considered potential candidate drugs for the treatment of HIV-1-infected individuals.