New piperazinyl polyazacyclophane scaffolds, libraries and biological activities

Strategies for the Design of Drugs Targeting RNA and RNA–Protein Complexes

“…[42±50] Small molecule inhibitors of the Tat ± TAR interaction have been obtained by rational design, [45] combinatorial synthesis, [43] high-throughput screening (HTS) assays, [44,46] and a combination of these approaches. [47] Structure-based design of ligands specific for TAR [45,50] will be greatly facilitated by the availability of three-dimensional structures of the free RNA, [51] the RNA complexed with argininamide, [52] and peptides derived from the Tat protein. [53] Interestingly, it has been found that in the red clover necrotic mosaic virus (RCNMV), transcriptional trans activation is mediated not by a protein but by an RNA specifically binding to a TAR-like element.…”

“…The majority of RNA-binding molecules (Figure 3) both natural, such as the aminoglycoside [191] and tuberactinomycin [91] antibiotics, and designed, including synthetic aminoglycoside derivatives and mimetics, [30, 49, 79, 128±132, 192] diphenylfurans, [77] cyclophanes, [47,193] macrocycles, [80] polyamine ± acridine conjugates, [45] arginine derivatives, [48,49] and peptoid/peptid oligom- Figure 3. A collection of RNA-binding compounds which specifically recognize different RNA folds (see text for further details): natural aminoglycoside antibiotics, neomycin B (1) and tobramycin (2); [191] simplified semisynthetic aminoglycoside mimetics, 3 and 4; [128,130] an aminol aminoglycoside surrogate 5; [131] natural tuberactinomycin antibiotics 6 (R 1 and/or R 3 are usually cationic substituents); [91] In-PRiNts 7; [45] photocleaving flavin derivatives 8; [204] a quinoxaline-2,3-dione derivative 9; [46] a 2,4-diaminoquinozaline derivative 10; [46] substituted diphenyl furans 11; [77] and piperazinyl polyazacyclophanes 12.…”

“…A collection of RNA-binding compounds which specifically recognize different RNA folds (see text for further details): natural aminoglycoside antibiotics, neomycin B (1) and tobramycin (2); [191] simplified semisynthetic aminoglycoside mimetics, 3 and 4; [128,130] an aminol aminoglycoside surrogate 5; [131] natural tuberactinomycin antibiotics 6 (R 1 and/or R 3 are usually cationic substituents); [91] In-PRiNts 7; [45] photocleaving flavin derivatives 8; [204] a quinoxaline-2,3-dione derivative 9; [46] a 2,4-diaminoquinozaline derivative 10; [46] substituted diphenyl furans 11; [77] and piperazinyl polyazacyclophanes 12. [47] Most of the compounds carry positive charges at physiological pH, however, protonation is indicated here only for the natural aminoglycosides, for which exact pK a values are available. [217] ers, [43] are cationic compounds carrying several positively charged groups.…”

The Synthesis of Macrocycles for Drug Discovery

“…61 Essentially the same strategy, using an S N 2 process to prepare the macrocycle followed by reaction of the amine with various electrophilic species, was employed to construct a variety of piperidinyl polyazacyclophane libraries (272, Figure 11.20, site of ring closure, base and leaving group employed indicated) containing four diversity sites. 364 Similarly, a series of 19-to 26-membered polyazadipyridinocyclophane scaffolds (273) was assembled as a screening collection of almost 25,000 compounds. 365 Perhaps not surprisingly, the yields in the macrocyclization decreased as the ring size increased, from 95% for the 19-membered ring (m ¼ 2, n ¼ 1) to 40% for the 26-ring size (m ¼ 6, n ¼ 4).…”

Chemical and functional diversity of small molecule ligands for RNA

“…110 Similar to the aminoglycosides, macrocyclic antibiotics such as the macrolides and streptogramins have served as templates for the design of novel potentially antibacterial and antiviral compound series targeted at RNA. Peptide chemistry or alkylation of amino functionalities have been used most frequently to construct synthetic macrocycles, including the antibacterial 14-membered amides 7, 111 and the 13-membered polyamines 8, 112 which were investigated as HIV-1 Tat-TAR inhibitors. The 14-membered macrocycles 7 yielded antibacterial compounds that inhibited in vitro translation assays, albeit their molecular target has not been determined.…”