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Design, Synthesis, Biological Evaluation and Silico Prediction of Novel Sinomenine Derivatives

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Design, Synthesis, Biological Evaluation and Silico Prediction of Novel Sinomenine Derivatives molecules Article Design, Synthesis, Biological Evaluation and Silico Prediction of Novel Sinomenine Derivatives Shoujie Li 1, Mingjie Gao 2, Xin Nian 3, Liyu Zhang 4, Jinjie Li 5 , Dongmei Cui 3,*, Chen Zhang 4,* and Changqi Zhao 1,* 1 Gene Engineering and Biotechnology Beijing Key Laboratory, College of Life Science, Beijing Normal University, 19 XinjiekouWai Avenue, Beijing 100875, China; [email protected] 2 Research Group Pharmaceutical Bioinformatics, Institute of Pharmaceutical Sciences, Albert-Ludwigs-Universität Freiburg, 79106 Freiburg im Breisgau, Germany; [email protected] 3 College of Pharmaceutical Science, Zhejiang University of Technology, 18 Chaowang Road, Hangzhou 310014, China; [email protected] 4 College of Pharmaceutical Sciences, Zhejiang University, 866 Yuhangtang Road, Hangzhou 310058, China; [email protected] 5 Beijing Key Laboratory of Bioactive Substances and Functional Foods, Beijing Union University, 197 Beitucheng West Road, Beijing 100191, China; [email protected] * Correspondence: [email protected] (D.C.); [email protected] (C.Z.); [email protected] (C.Z.); Tel.: +86-010-58805046 (Changqi Zhao) Abstract: Sinomenine is a morphinan alkaloid with a variety of biological activities. Its derivatives have shown significant cytotoxic activity against different cancer cell lines in many studies. In this study, two series of sinomenine derivatives were designed and synthesized by modifying the active Citation: Li, S.; Gao, M.; Nian, X.; positions C1 and C4 on the A ring of sinomenine. Twenty-three compounds were synthesized and Zhang, L.; Li, J.; Cui, D.; Zhang, C.; characterized by spectroscopy (IR, 1H-NMR, 13C-NMR, and HRMS). They were further evaluated Zhao, C. Design, Synthesis, Biological for their cytotoxic activity against five cancer cell lines, MCF-7, Hela, HepG2, SW480 and A549, and Evaluation and Silico Prediction of a normal cell line, Hek293, using MTT and CCK8 methods. The chlorine-containing compounds Novel Sinomenine Derivatives. exhibited significant cytotoxic activity compared to the nucleus structure of sinomenine. Furthermore, Molecules 2021, 26, 3466. https://doi.org/10.3390/ we searched for cancer-related core targets and verified their interaction with derivatives through molecules26113466 molecular docking. The chlorine-containing compounds 5g, 5i, 5j, 6a, 6d, 6e, and 6g exhibited the best against four core targets AKT1, EGFR, HARS and KARS. The molecular docking results were Academic Editor: consistent with the cytotoxic results. Overall, results indicate that chlorine-containing derivatives Giovanni Palmisano might be a promising lead for the development of new anticancer agents. Received: 9 May 2021 Keywords: sinomenine; synthesis; cancer; cytotoxic activity; docking study Accepted: 2 June 2021 Published: 7 June 2021 Publisher’s Note: MDPI stays neutral 1. Introduction with regard to jurisdictional claims in Natural products, also known as secondary metabolites, are organic compounds with published maps and institutional affil- biological functions and activities synthesized by microorganisms or plants in their cells. iations. They play an irreplaceable role and have broad application prospects in pharmaceutical, agricultural, chemical industries and other fields [1,2]. In fact, 6.1% of the total 1394 small molecule drugs developed from 1981 to 2019 were natural compounds, and 27.5% were de- veloped by structural optimization. Furthermore, small molecule cancer drugs developed Copyright: © 2021 by the authors. between 1940 and 2019 are directly or indirectly derived from natural products [3]. Licensee MDPI, Basel, Switzerland. Alkaloids are nitrogen-containing organic compounds widely found in plants, ani- This article is an open access article mals and microorganisms. Most alkaloids have complex structures with basic nitrogen- distributed under the terms and containing heterocycles. A few alkaloids are organic amine alkaloids in which nitrogen conditions of the Creative Commons atoms are absent in the ring structure. Thus far, around 12,000 alkaloids have been isolated Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ from nature [4]. Based on their source or chemical structure, the alkaloids are divided 4.0/). into about 60 categories, including tropine, isoquinoline, indole alkaloids, terpenoids and Molecules 2021, 26, 3466. https://doi.org/10.3390/molecules26113466 https://www.mdpi.com/journal/molecules Molecules 2021, 26, 3466 2 of 27 from nature [4]. Based on their source or chemical structure, the alkaloids are divided into about 60 categories, including tropine, isoquinoline, indole alkaloids, terpenoids and ste- roidal alkaloids. Tropine alkaloids contain a tropinyl skeleton which is formed by the combination of pyrrole and piperidine rings [5]. Isoquinoline alkaloids, such as papaver- ine, tetrandrine, berberine, sanguinarine, sinomenine and lycorine, are derived from the phenylalanine and tyrosine pathways based on isoquinoline or tetrahydroisoquinoline [6– 10]. Indole alkaloids, such as vinblastine and vincristine have indole skeletons and com- plex structures [11]. Terpenoids and steroidal alkaloids such as dendrobine, aconitine, and peiminine have a terpenoid or steroidal structure [12,13]. Alkaloids are well known for their high efficiency and low toxicity in antitumor activity. The dry canes of Sinomenium acutum (Thunb.) Rehd. et Wils. and Sinomenium acutum (Thunb.) Rehd. et Wils. var. cinereum Rehd. et Wils., also known as Qingfeng Teng in tra- ditional Chinese medicine, have been used in the treatment diseases [14]. In the 1920s, sinomenine was isolated from Qing Feng Teng (Japanese sabia stem) grown in Japan [15]. Several studies reported that sinomenine (an isoquinoline alkaloid monomer) carrying a phenanthrene nucleus and ethylamine bridge, has a structure is similar to the narcotics morphine and codeine. Its chemical structure is shown in Figure 1. In previous work, structural modification of sinomenine was carried out in the active groups of its four rings [9]. The A ring is a benzene ring where C3 and C4 are substituted by methoxy and hydroxyl groups. Structural modification on the A ring is often present on the active reaction sites C1 and C4, and sometimes on C2 or C3, but it is relatively rare Molecules 2021, 26, 3466 [16]. Different sinomenine derivatives were reported in the previous studies as having2 of 25 good anti-inflammatory, immunosuppressive and neuroprotective activities compared to sinomenine [17]. In this study, we designed and synthesized two new series of sinomine derivatives in a quest to obtain potent compounds. steroidal alkaloids. Tropine alkaloids contain a tropinyl skeleton which is formed by the Many scholars have reported the structural modification of the sinomenine A ring. combination of pyrrole and piperidine rings [5]. Isoquinoline alkaloids, such as papaverine, Due to the good application effect of piperidine and tetrahydropyrrole in medicine, we tetrandrine, berberine, sanguinarine, sinomenine and lycorine, are derived from the pheny- took sinomenine as the leading compound and introduced piperidine methylene or tetra- lalanine and tyrosine pathways based on isoquinoline or tetrahydroisoquinoline [6–10]. hydropyrrole methylene at C1 by Mannich reaction to obtain 1-piperidine methylated si- Indole alkaloids, such as vinblastine and vincristine have indole skeletons and complex nomenine (5a–5k) and 1-tetrahydropyrrole methylated sinomenine (6a–6l) [18]. As the structures [11]. Terpenoids and steroidal alkaloids such as dendrobine, aconitine, and peimininephenolic hydroxyl have a terpenoidgroup of C or4 is steroidal easy to oxidize structure and [12 decompose,13]. Alkaloids and may are wellbe a factor known lead- for theiring to high allergic efficiency reactions and in low vivo, toxicity it is necess in antitumorary to modify activity. the structure to protect the phe- nolicThe hydroxyl dry canes group. of Sinomenium Esters are important acutum (Thunb.) intermediates Rehd. of et organic Wils. and synthesis.Sinomenium The acutumphenol (Thunb.)hydroxyl ester Rehd. can et not Wils. only var. increasecinereum liposoluRehd.bility, et Wils., enhance also substance known as activity Qingfeng and Teng change in traditionalmetabolic characteristics, Chinese medicine, but it have can beenalso sl usedow down in the the treatment oxidation diseases rate of [ 14compounds]. In the 1920s, and sinomeninegreatly reduce was their isolated allergic from reactions. Qing Feng Theref Tengore, (Japanese a series sabiaof 1,4-bi stem)substituted grown in sinomenine Japan [15]. Severalderivatives studies were reported synthesized that sinomenineby the reaction (an of isoquinoline phenylacetyl alkaloid chloride monomer) with 1-tetrahydro- carrying a phenanthrenepyrrole methylated nucleus sinomenine. and ethylamine All structures bridge, of has the a products structure were is similar determined to the by narcotics IR, 1H- morphineNMR, 13C-NMR, and codeine. and HRMS. Its chemical structure is shown in Figure1. Figure 1. The structures of sionmenine,sionmenine, morphine and codeine. InFurthermore, previous work, the structuralcytotoxicity modification of the synthesized of sinomenine compounds was carried was outassessed. in the activeCom- groupspounds of5a its–5k four were rings tested [9]. against The A ringthree is cancer a benzene cell lines, ring whereMCF-7, C 3Hela,and Cand4 are HepG2, substituted using bythe methoxyMTT method. and hydroxyl Compounds groups. 6a– Structural6l were
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