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Background/Objectives: Current promising treatments for many diseases are based on the use of therapeutic nucleic acids, including DNA. However, the list of nanocarriers is limited due to their low biocompatibility, high cost, and toxicity. The design of synthetic building blocks for creating universal delivery systems for genetic material is an unsolved problem. In this work, we propose PAMAM dendrimers with rigid thiacalixarene core in various conformations, i.e., PAMAM-calix-dendrimers, as a platform for a supramolecular universal constructor for nanomedicine. Results: Third generation PAMAM dendrimers with a macrocyclic core in three conformations (cone, partial cone, and 1,3-alternate) were synthesized for the first time. The obtained dendrimers were capable of binding and compacting calf thymus DNA, whereby the binding efficiency improved with increasing generation, while the influence of the macrocyclic core was reduced. A dramatic effect of the macrocyclic core conformation on the hemolytic activity of PAMAM-calix-dendrimers was observed. Specifically, a notable reduction in hemotoxicity was associated with a decrease in compound amphiphilicity. Conclusions: We hope the results will help reduce financial and labor costs in developing new drug delivery systems based on dendrimers. [ABSTRACT FROM AUTHOR]

Reversible cholinesterase (ChE) inhibitors are widely used drugs for the therapy of various cognitive and neurodegenerative disorders. The development of a "universal drug" with easily tunable ChE inhibition activity is a relevant interdisciplinary problem. Here we propose for the first time the design of novel "fine-tuned" ChE inhibitors based on dendrimers with a thiacalix[4]arene core (PAMAM-calix-dendrimers). A series of first-generation PAMAM-calix-dendrimers with different terminal fragments were designed and synthesized. The human acetylcholinesterase and butyrylcholinesterase inhibition by PAMAM-calix-dendrimers was confirmed by molecular docking and in vitro studies. PAMAM-calix-dendrimers were found to have IC 50 values for acetylcholinesterase and butyrylcholinesterase in the range of 0.076-5400 μM. Relationships between the structure of PAMAM-calix-dendrimers and the ChE inhibitory activity were established. The conformation of the macrocyclic core and the nature of the terminal groups were found to exert a direct impact on the inhibitory activity of dendrimers. We anticipate our study to be a starting point for creation of "universal drug" with tunable ChE inhibitory activity to specific therapeutic targets, and more sophisticated in vivo studies of such systems., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)