Please cite this article as: Fumagalli, G., Marucci, C., Christodoulou, M.S., Stella, B., Dosio, F., Passarella, D.,Self-assembly drug conjugates for anticancer treatment, Drug Discovery Today (2016), http://dx.doi.org/10.1016/j.drudis. 2016.06.018 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. A c c e p t e d M a n u s c r i p t Keywords: Self-assembly; drug conjugate; nanoparticle. Self-assembly drug conjugates for anticancer treatmentTeaser: In this review we summarize the recent advances in nanoparticles obtained by self-assembly drug conjugates, a useful tool to improve drug delivery of anticancer compounds. Page 4 of 25A c c e p t e d M a n u s c r i p tSelf-assembly drug conjugate preparation is a promising approach to improve activity and penetration through physiological barriers of potent small molecules, as well as to reduce any side effects. Drug conjugates can self-assemble in water to form nanoparticles (NPs) that offer several advantages because: (i) they are easy to obtain; (ii) they can reach high local drug concentration in tumor tissues; and (iii) they can reduce the side effects of drugs. All these factors improve drug pharmacokinetic properties. Here, we have reviewed the scope of nanotechnology-based self-assembly drug delivery approaches focusing on prodrugs able to form NPs by self-assembly; we have also summarized the current perspective and challenges facing the successful treatment of cancer.

The ability of 4-(1,2-diphenylbut-1-en-1-yl)aniline as a self-assembly inducer is reported. The conjugation of this moiety with aloin or podophyllotoxin resulted in spherical nanoparticles that were characterized by Dynamic Light Scattering (DLS), Transmission Electron Microscopy (TEM) and NanoSight technology. A preliminary biological evaluation on two cancer cell lines is reported.

The synthesis of the eight stereoisomers of 6-[2-methoxy-3-(piperidinyl)propyl]-5,6-dihydropyran-2-one is reported. The configuration at C2′ and C6 is induced by a sterecontrolled allylation reaction with DIP-Cl. The general structure is the result of merging the structures of two natural products (pironetin and dumetorine) with the aim of discovering a new scaffold for tubulin binders. Docking studies and biological evaluations confirm the validity of the approach

The development of modern technologies casts a new light on the natural products as an invaluable source of lead compounds that could guide drug discovery. Cancer stem cells are a subpopulation of cancer cells with a high clonogenic capacity and the ability to reform the parental tumours upon transplantation. They have been proposed to drive tumorigenesis and metastases. In this review, we present the ability of forty-nine different natural products to influence the biology of cancer stem cells.

Four different hybrid compounds have been efficiently synthesized by conjugation of deacetylthiocolchicine with pironetin‐inspired derivatives. The modest bioactivity and the apparent absence of interaction with α‐tubulin is explained by a posteriori in silico investigation, which suggests a relevant distance between the thiocolchicine binding site and the proper pocket on the α‐tubulin. The modest activity on resistant cells suggested that the lipophilic nature of the linker used renders the resulting compounds better substrates for p‐Gp efflux pumps. The study better clarifies the design of bivalent compounds that target hetero tubulin/microtubules.