Introduction Endocytosis, Dynamin and Diseases

Proceedings of MatricesFor IITTEP – ICoMaNSEd 2015 ISBN: 978-602-74204-0-3 Chemistry Page 130 STRUCTURE-ACTIVITY RELATIONSHIP SAR OF ENDOCYTOSIS INHIBITORS Dian H.O. Howan 1 1 Chemistry Department, Faculty of Mathematics and Natural Science, State University of Manado, Minahasa, Indonesia dian_octorinayahoo.com Abstract: Endocytosis is the process of cells take up extracellular materials and recycles their membrane. This process happens in almost all living eukaryotic cells by several mechanisms that can be divided into two types, namely: phagocytosis, and pinocytosis. Endocytosis plays significant roles in many pathological conditions. There are over 100 known diseases involving endocytosis and intracellular trafficking. A number of endocytosis researches has been conducted, and generated some compounds with great inhibitor value. The inhibitors namely: dynasore, bis-T, MiTMAB, Indole analogues, and phthalamide analogues. This paper will discuss the structure-activity relationship profiles of these inhibitors. Keywords: Endocytosis, structure-actity relationship, inhibitors, dynamin

1. Introduction

Endocytosis is the process whereby cells take up extracellular material and recycle their membranes Cousin et al , 2001. It happens in almost all living eukaryotic cells by several mechanisms that can be divided into two types, namely, phagocytosis, which occurs only in specialised mammalian cells and pinocytosis, which occurs in all cells is regulated by intracellular and extracellular signals Liu et al , 1995; Conner et all , 2003. Phagocytosis is the process that occurs when cells uptake the large particles, while pinoctytosis is the process of taking up fluid and solutes. Furthermore, pinocytosis can be divided into two mechanisms, clathrin mediated endocytosis CME and clathrin-independent endocytosis Liu et al , 1995. One of enzymes that involves in endocytosis process is dynamin Mousavi et al , 2004.

2. Endocytosis, Dynamin and Diseases

Endocytosis plays significant roles in many of human pathological conditions. There are over 100 known diseases involving endocytosis and intracellular trafficking Aridor Hannan, 2002; Aridor Hannan, 2000.. Control of endocytosis through the inhibition of dynamin could be useful in the treatment of cancer; viral, bacterial and other pathogenic infections; immunodeficiency, gastrointestinal, neurodegenerative, neurological and kidney diseases. Several studies revealed some diseases that are connected to dynamin, such as Charcot-Marie- Tooth CMT disease Zuchner et al , 2005, Centronulear myopathy CNM Bitoun et al , 2005, and Papillomaviruses, HPV16 and BPV1 – the etiologic agent of cervical and anal cancers and of tumors and disease in animals Abban et al , 2008 Several neurodegenerative diseases are associated with dynamin-dependent endocytic trafficking pathways. These include Alzheimer’s disease, Huntington’s disease HD, stiff- person syndrome, Lewy body dementians, and Niemann-Pick type C disease Aridor Hanna n, 2002. The presynaptic α-synuclein protein is believed to be involved in Lewy body diseases, including Parkinson’s disease, Lewy body dementia and a Lewy body variant of Proceedings of MatricesFor IITTEP – ICoMaNSEd 2015 ISBN: 978-602-74204-0-3 Chemistry Page 131 Alzheimer’s disease Sung et al , 2001. Furthermore, these pathologies were found to be a direct consequence of α-synuclein endocytosis suggesting that endocytosis inhibitors may be useful in the treatment of α-synuclein related disorders.

3. Structur-Activity Relationship SAR of Dynamin Endocytosis Inhibitors