Antitumor agents 269. Non-aromatic ring-A neotanshinlactone analog, TNO, as a new class of potent antitumor agents

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In our exploration of new biologically active chemical entities, we designed and synthesized a novel class of antitumor agents, substituted 4-amino-7,8,9,10-tetrahydro-2H-benzo[h]chromen-2-one (ATBO) analogs. We evaluated their cytotoxic activity against seven human tumor cell lines from different tissues, and established preliminary structure-activity relationships (SAR). All analogues, except 8, 9, and 25-27, displayed potent tumor cell growth inhibitory activity. Especially, compounds 15 and 33 with a 4-methoxyphenyl group at position C-4 were extremely potent with ED 50 values of 0.008-0.064 μM and 0.035-0.32 μM, respectively. Compound 15 was the most potent analog compared with structurally related neo-tanshinlactone (e.g., 1) and 4-amino-2H-benzo[h]chromen-2-one (ABO, e.g., 4) analogs, and thus merits further exploration as an anti-cancer drug candidate. -7,8,9,10-tetrahydro-2H-benzo[h]chromen-2-ones (ATBO); Cytotoxic activity; Neotanshinlactone One of the most challenging areas of research in both industry and academia is the discovery and development of new medicines. Publisher's Disclaimer: 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 citable 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. Keywords 4-Amino NIH Public Access Author ManuscriptBioorg Med Chem Lett. Author manuscript; available in PMC 2012 January 1. greater.4 These facts prompted us to design and discover new biologically active chemical entities.Previously, our group successfully developed new cytotoxic chemical entities, including neotanshinlactone (1, Figure 1) and its 4-ethyl analog 2,5 , 6 for treating breast cancer, and these compounds are now in extended preclinical study. Structural simplification and optimization is a powerful tool for analog design and lead exploration. For example, this strategy was applied to the natural product halichondrin B, a potent mitotic inhibitor, which led to a new therapeutic medicine, eribulin mesylate. 7 In our continuous exploration of new chemical entities, we also designed and developed several additional series of novel anticancer agents according to this strategy. These agents include 2-(furan-2-yl) naphthalen-1-ol (FNO), 8 6-phenyl-4H-furo[3,2-c]pyran-4-one (AFPO), 9 tetrahydronaphthalene-1-ol (TNO),10 and 4-amino-2H-benzo[h]chromen-2-one (ABO, 3 , Figure 1) 11 analogs. Lead compounds showed potent antitumor activity and different tumor tissue type selectivity. Braccio et al first reported four compounds with the ABO scaffold and their cytotoxic activity against Ehrlich ascites tumor cells. 12 We also designed and explored this scaffold based on our studies of neo-tanshinlactone analogs (1, 2). Compound 4 showed potent a...

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Antitumor agents 281. Design, synthesis, and biological activity of substituted 4-amino-7,8,9,10-tetrahydro-2H-benzo[h]chromen-2-one analogs (ATBO) as potent in vitro anticancer agents

Dong

Nakagawa‐Goto

Lai

et al. 2011

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“…2.3 Moreover, 2 was selective for a subset of breast cancer-derived cell lines and significantly less active against normal breast-derived tissue. In order to explore the effect of individual rings on the anticancer activity, identify new lead compounds, and discover new chemical entities, we designed and reported five classes of new anticancer agents, including 2-(furan-2-yl)naphthalen-1-ol (FNO),4 6-phenyl-4 H -furo[3,2- c ]pyran-4-one (AFPO),5 tetrahydronaphthalene-1-ol (TNO),6 4-amino-2 H -benzo[ h ]chromen-2-one (ABO, 3 , Figure 1),7 and 4-amino-7,8,9,10-tetrahydro-2 H -benzo[ h ]chromen-2-one (ATBO, 4 , Figure 1)8 analogs. Interestingly, the neo-tanshinlactone-inspired synthesis of a breast cancer selective ABO series was reported independently by others 9…”

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confidence: 99%

Antitumor agents 287. Substituted 4-amino-2H-pyran-2-one (APO) analogs reveal a new scaffold from neo-tanshinlactone with in vitro anticancer activity

Dong

Nakagawa‐Goto

Lai

et al. 2011

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4-Amino-2H-benzo[h]chromen-2-one (ABO) and 4-amino-7,8,9,10-tetrahydro-2H-benzo[h]chromen-2-one (ATBO) analogs were found to be significant in vitro anticancer agents in our previous research. Our continuing study has now discovered a new simplified (monocyclic rather than tricyclic) class of cytotoxic agents, 4-amino-2H-pyran-2-one (APO) analogs. By incorporating various substituents on the pyranone ring, we have established preliminary structure-activity relationships (SAR). Analogs 19, 20, 23, and 26–30 displayed significant tumor cell growth inhibitory activity in vitro. The most active compound 27 exhibited ED50 values of 0.059–0.090 μM.

“…As shown in Scheme 1, carboxylic acids 5 and 6 , synthesized by the method reported before,4 were converted to esters 7, 8 , and 12 , respectively, with thionyl chloride and the appropriate alcohols at room temperature 5. In addition, treatment of 5 with Lawesson’s reagent led to methylthioate 9 ,3 with methanamine to amide 10 , and with hydroxybenzotriazole (HOBt) to benzotriazole ester 11 .…”

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Antitumor agents 279. Structure–activity relationship and in vivo studies of novel 2-(furan-2-yl)naphthalen-1-ol (FNO) analogs as potent and selective anti-breast cancer agents

Dong¹,

Nakagawa‐Goto²,

Lai³

et al. 2011

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In our ongoing modification study of neo-tanshinlactone (1), we discovered 2-(furan-2-yl)naphthalen-1-ol (FNO) derivatives 3 and 4 as a new class of anti-tumor agents. To explore structure-activity relationships (SAR) of this scaffold, 18 new analogs, 6-12 and 14-24, were designed and synthesized. The C11-esters 7 and 12 displayed broad anti-tumor activity (ED 50 1.1-4.3 µg/mL against seven cancer cell lines), while C11-hydroxymethyl 14 showed unique selectivity against the SKBR-3 breast cancer cell line (ED 50 0.73 µg/mL). Compounds 15 and 22 displayed potent and selective anti-breast tumor activity (ED 50 1.7 and 0.85 µg/mL, respectively, against MDA-MB-231). The SAR results demonstrated that the substitutions from the ring-opened lactone ring C of 1 are critical to the anti-tumor potency as well as the apparent tumor-tissue type selectivity. Treatment with 3 in Brca1 f11/f11 p53 f5&6/f5&6 Cre c mice models significantly inhibited the proliferation of mammary epithelial cells and branching of mammary glands.Keywords 2-(furan-2-yl)naphthalen-1-ol analogs; structure-activity relationships; anti-breast tumor agents Neo-tanshinlactone (1), a natural product from Salvia miltiorrhiza, and its analog, 4-ethyl neo-tanshinlactone (2), are potent and selective anti-breast cancer agents (Figure 1). [1][2][3] In our prior studies, they exhibited high tumor tissue-type as well as breast cancer cell line selectivity. The selective anti-breast tumor activity of 2 in mice models is consistent with the Publisher's Disclaimer: 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 citable 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. NIH Public Access Author ManuscriptBioorg Med Chem Lett. Author manuscript; available in PMC 2012 January 1. 3 In our continuing study, we explored how the individual rings A-D in the molecule influence the in vitro anti-breast tumor activity. The results led to the discovery of a novel class of anti-breast cancer agents, 2-(furan-2-yl)naphthalen-1-ol (FNO) analogs (e.g., 3 and 4) by opening ring-C. 4 Our previous studies also explored the preliminary SAR and proved that the C8 and C11 substituents can greatly affect both potency and selectivity. FNO analog 3 showed significant potency (ED 50 0.3 µg/mL) and selectivity against the ZR-7-51 (ER+, HER2+) cell line compared with other cancer cell lines tested, while 4 exhibited activity against all cancer cell lines tested. 4 We wanted to use these promising results to design novel analogs with better pharmaceutical profiles and develop them as clinical trials candidates.The initial studies showed that Et, H, and Me groups are preferred at the C4, C14, and C15 positions, respectively, ...