Microtubule-targeting agents (MTAs) are some of the clinically most successful anti-cancer drugs. Unfortunately, instances of multidrug resistances to MTA have been reported, which highlights the need for developing MTAs with different mechanistic properties. One less explored class of MTAs are [1,2,4]triazolo[1,5-a]pyrimidines (TPs). These cytotoxic compounds are microtubule-stabilizing agents that inexplicably bind to vinblastine binding site on tubulin, which is typically targeted by microtubule-destabilizing agents. Here we used cellular, biochemical, and structural biology approaches to address this apparent discrepancy. Our results establish TPs as vinca-site microtubule-stabilizing agents that promote longitudinal tubulin contacts in microtubules, in contrast to classical microtubule-stabilizing agents that primarily promote lateral contacts. Additionally we observe that TPs studied here are not affected by p-glycoprotein overexpression, and suggest that TPs are promising ligands against multidrug-resistant cancer cells.
Qualitative conformational analysis of the entirety of conceivable hexo-and pentopyranosyl oligonucleotide systems derived from the diastereoisomeric aldohexoses (CH,0)6 and aldopentoses (CH20), predicts the existence of a variety of pairing systems which have not been experimentally investigated so far. In particular, the analysis foresees the existence of a ribopyranosyl isomer of RNA ('p-RNA'), containing the phosphodiester linkage between the positions C(4) and C(2') of neighboring ribopyranosyl units. Double strands of p-RNA oligonucleotides are expected to have a linear structure and to show purine-pyrimidine and purine-purine (WatsonCrick) pairing comparable in strength to that observed in homo-DNA. Experimentally, synthetic fl-D-ribopyranosy1 (4+2')-oligonucleotides derived from adenine and uracil confirm this prognosis: adenine-uracil pairing in p-RNA duplexes is stronger than in the corresponding RNA duplexes. Importantly, adenine in p-Ribo(A,) does not show (reverse-Hoogsleen) self-pairing, in sharp contrast to its behavior in the homo-DNA series. The sheer existence of strong and selective pairing in a system that is constitutionally isomeric to RNA and can be predicted to have a linear structure has implications for the problem of RNA's origin. In this context, a comprehensive experimental study of the pairing properties of p-RNA, of its potential for constitutional assembly, self-replication, and intra-duplex isomerization to RNA seems mandatory.
In memoriam Rolf Scheffold (1. IX.95) Base pairing in p-RNA @ -o-ribopyranosyl-(4 + 2)-oligonucleotides) is not only stronger than in DNA and RNA, but also more selective in the sense that it is strictly confined to the Watson-Crick mode. Homopurine sequences (tested up to decamers) exist as single strands under conditions where they undergo reverse-Hoogsteen self-pairing in homo-DNA or Hoogsfeen self-pairing in DNA. This exceptional pairing selectivity is rationalized as hinging on two structural features of p-RNA: the large inclination between backbone axis and base-pair axes in p-RNA duplexes, and the higher rigidity of the p-RNA backbone compared with RNA, DNA, and homo-DNA. The most important consequence of the pairing selectivity refers to the potential of p-RNA to replicate. Replicative copying of sequence information by nonenzymatic template-controlled ligation is not hampered by self-pairing of guanine-rich templates, as it is known to be the case in the RNA series. We have demonstrated two replicative cycles in which G-rich p-RNA-octamer templates induce sequence-selective ligation of tetramer-2'-phosphate derivatives to complementary C-rich octamer sequences, and in which the latter, with comparable efficiency, induce corresponding ligation reactions back to the original G-rich octamers. Ligation is most satisfactorily achieved after pre-activation of the 2'-phosphate groups as 2',3'-cyclophosphate derivatives; in this version, the process does not proceed as oligocondensation, but as a genuine oligomerization. This is of considerable promise for the search for potentially natural conditions under which homochiral p-RNA strands might self-assemble and self-replicate.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.