Contents lists available at ScienceDirect Bioorganic Chemistry journal homepage: www.elsevier.com/locate/bioorg New AChE inhibitors from microbial transformation of trachyloban-19-oic acid by Syncephalastrum racemosum Gabriel Franco dos Santos a , Gesiane da Silva Lima a , Geane Pereira de Oliveira a , José Dias de Souza Filho a , Luciana da Silva Amaral b , Edson Rodrigues-Filho b , Jacqueline Aparecida Takahashi a, ⁎ a Universidade Federal de Minas Gerais (UFMG), Departamento de Química, Av. Antonio Carlos, 6627, CEP 31270-901 Belo Horizonte, MG, Brazil b Universidade Federal de São Carlos (UFSCar), Departamento de Química, Rodovia Washington Luís, s/n, CEP 13565-905 São Carlos, SP, Brazil ARTICLE INFO Keywords: Syncephalastrum racemosum Biotransformation Trachyloban-19-oic acid Acetylcholinesterase Alzheimer’s disease ABSTRACT Trachyloban-19-oic acid (1) is a diterpene very abundant in nature and its structural modification can furnish new bioactive compounds. Biotransformation of 1 by fungus Syncephalastrum racemosum provided three deri- vatives, two hydroxylated products (2–3) and one product of rearrangement (4). Products 3 and 4 have never been reported so far, to the best of our knowledge. Structure of 3 was formed after oxidation and rearrangement of compound 2. Compounds 1–4 were evaluated for inhibition of acetylcholinesterase, enzyme linked to the symptomatic control of Alzheimer’s disease. All the compounds presented inhibitory activity higher than starting material 1, and product 3 presented IC 50 = 0.06 μM, which is about six times higher than activity found for galanthamine (IC 50 = 0.38 μM), the positive control used in this assay. 1. Introduction Fungi are an inexhaustible source of natural products mainly due to their wide distribution in the nature, estimated to range from 1.5 to 5.1 million species in the world [1]. Secondary metabolites from fungi represent a substantial fraction of drugs and drug models in pharmaceutical industries, including antibiotics, statins and im- munosuppressant [2,3]. Fungal biosynthetic routes used to produce secondary metabolites are also useful to undertake structural mod- ifications in xenobiotic compounds. Biotransformation is a tool that has been extensively used to prepare derivatives from trachylobane diterpenes. Trachyloban-19-oic acid (1), a natural diterpene found in plants of different genera such as Croton [4], Xylopia [5,6], Arctopus [7], Iostephane [8], and Helianthus [9], is a promisor substrate for preparing new bioactive derivatives. Biotransformation by fungi has attracted great interest to the pharmaceutical, chemical and food industries due of numerous ad- vantages, mainly the capacity of performing chemo-, regio- and enantio- selective reactions [10,11]. In trachylobane diterpenes, bio- transformation most commonly leads to hydroxylation and skeleton rearrangement. Hydroxylation has been accomplished at several posi- tions such as C-7β and C-17 [12] and C-11β [13] using Rhizopus stolo- nifer, C-1α and C-17 using Rhizopus arrhizus [14], C-19 using Gibberella fujikuroi [15], and at C-7β using Mucor plumbeus (Fig. 1) [16]. In addition, rearrangements of trachylobane into kauranes di- terpenes by R. stolonifer were described [12,13]; in this case, the covalent bond between C-12 and C-16 is disrupted, with formation of a C-16 tertiary carbocation, which is subsequently hydrated. Thus, tra- chylobane skeleton is pointed as the precursor of ent-kaur-1l-ene deri- vatives [9]. Another rearrangement found in the literature from tra- chylobane diterpenes lead to the formation of trachylobagibberellins by G. fujikuroi [9,17]. Formation of trachylobagibberellins involves an oxidation of C-19 followed by hydroxylation at C-7 and contraction of ring B with C-7 extrusion. In the biotransformation of ent-trachyloban- 18-oic acid by R. arrhizus another type of rearrangement was described, in which the bond between C-13 and C-16 was disrupted and a new bond was created between C-11 and C-13, followed by formation a double bond between C-15 and C-16 [14]. In a previous work [16], trachyloban-19-oic acid (1) and derivatives showed acetylcholinesterase inhibition, raising our interest to prepare further derivatives for biological screening, since new drug leads for treatment of Alzheimer’s disease are very welcome worldwide. There- fore, we report herein the biotransformation of trachyloban-19-oic acid (1) by S. racemosum into one known and two new products: 17-hy- droxytrachyloban-19-oic acid (2), trachyloban-17,19-dioic acid (3) and ent-16β,17-dihydroxykaur-11-en-19-oic acid (4), respectively. S. https://doi.org/10.1016/j.bioorg.2018.04.011 Received 10 February 2018; Received in revised form 12 April 2018; Accepted 13 April 2018 ⁎ Corresponding author. E-mail address: jat@qui.ufmg.br (J.A. Takahashi). Bioorganic Chemistry 79 (2018) 60–63 Available online 16 April 2018 0045-2068/ © 2018 Elsevier Inc. All rights reserved. T