neotanshinlactone and Breast-Neoplasms

6-Phenyl-4H-furo[3,2-c]pyran-4-one derivatives based on neo-tashinlactone (1) were synthesized and evaluated as novel anti-breast cancer agents. Compounds 10-13, 23, 25, and 27 showed potent inhibition against the SK-BR-3 breast cancer cell line. Importantly, 25 and 27 showed the highest cancer cell line selectivity, being approximately 100-250-fold more potent against SK-BR-3 (ED(50) 0.28 and 0.44microM, respectively) compared with other cancer cell lines tested. In addition, 25 displayed low cytotoxicity against normal breast cell lines 184A1 and MCF10A. Compounds 25 and 27 merit further investigation in our continuing program to generate and develop selective anti-breast cancer agents.

Topics: Antineoplastic Agents; Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Female; Humans; Molecular Structure; Pyrones; Structure-Activity Relationship

Neo-tanshinlactone (1) and its previously reported analogues, such as 2, are potent and selective in vitro antibreast cancer agents. The synthetic pathway to 2 was optimized from seven to five steps, with a better overall yield. Structure-activity relationships studies on these compounds revealed some key molecular determinants for this family of antibreast agents. Several derivatives (19-21 and 24) exerted potent and selective antibreast cancer activity with IC(50) values of 0.3, 0.2, 0.1, and 0.1 microg/mL, respectively, against the ZR-75-1 cell lines. Compound 24 was 2- to 3-fold more potent than 1 against SK-BR-3 and ZR-75-1. Importantly, 21 exhibited high selectivity; it was 23 times more active against ZR-75-1 than MCF-7. Compound 20 had an approximately 12-fold ratio of SK-BR-3/MCF-7 selectivity. In addition, analogue 2 showed potent activity against a ZR-75-1 xenograft model, but not PC-3 and MDA-MB-231 xenografts, as well as high selectivity against breast cancer cell line compared with normal breast tissue-derived cell lines. Further development of lead compounds 19-21 and 24 as clinical trial candidates is warranted.

Topics: Animals; Antineoplastic Agents; Breast Neoplasms; Cell Line, Tumor; Cell Survival; Female; Furans; Humans; Magnetic Resonance Spectroscopy; Male; Mass Spectrometry; Mice; Mice, SCID; Pyrones; Structure-Activity Relationship; Xenograft Model Antitumor Assays

Tetrahydroneotanshinlactone (TNT) and tetrahydronaphthalene-1-ol (TNO) derivatives were designed, synthesized, and evaluated for cytotoxic activity. The TNO derivatives were found to be a promising novel class of in vitro antitumor agents. The cyclohexene ring-A could dramatically affect the antitumor activity and selectivity. Compound 20 showed the highest potency with ED(50) values of 0.7 and 1.7 microM against SK-BR-3 and ZR-75-1 breast cancer cell lines, respectively.

Topics: Animals; Antineoplastic Agents; Antineoplastic Agents, Phytogenic; Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Drug Design; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor; Furans; Humans; Lung Neoplasms; Mice; Mice, Nude; Molecular Structure; Pyridazines; Pyrones; Structure-Activity Relationship

In our previous study, neo-tanshinlactone (1) showed potent and selective anti-breast cancer activity. To explore the SAR of 1, nine analogues (15-18, 24-28) were designed and synthesized. Together with 1 and tamoxifen (TAM), all newly synthesized compounds and some intermediates were evaluated for in vitro anticancer activity against several human tumor cell lines. Compounds without a ring D did not show promising activity, while compounds with a methylated furan ring D showed better activity than those with unsubstituted furan or hydroxy-dihydrofuran rings. Among all newly synthesized compounds, compound 15 with an ethyl group at the 4-position showed the best activity and selectivity with ED50 values of 0.45 and 0.18 microg/mL against MCF-7 and ZR-75-1 (ER+) and 13.5 and 10.0 microg/mL against MDA MB-231 and HS 587-1 (ER-), respectively. Furthermore, 15 also showed potent activity against SK-BR-3 (ER-, HER2+) with an ED50 value of 0.10 microg/mL. Our preliminary SAR studies showed that a methylated furan ring D and the C-4 substituent in ring A are critical for anti-breast cancer activity. Further development of 1 and 15 as anti-breast cancer drug candidates is warranted.

Topics: Antineoplastic Agents; Breast Neoplasms; Cell Line, Tumor; Drug Screening Assays, Antitumor; Female; Furans; Heterocyclic Compounds, 4 or More Rings; Humans; Pyrones; Structure-Activity Relationship

Neo-tanshinlactone (1) was isolated and synthesized for the first time and evaluated in vitro against several human cancer cell lines. Compound 1 showed significant inhibition against two ER+ human breast cancer cell lines and was 10-fold more potent and 20-fold more selective as compared to tamoxifen citrate. Compound 1 also potently inhibited an ER-, HER-2 overexpressing breast cancer cell line. Therefore, this novel compound merits further development as an anti-breast cancer drug candidate.

Topics: Antineoplastic Agents, Phytogenic; Breast Neoplasms; Cell Line, Tumor; Drug Screening Assays, Antitumor; Female; Furans; Humans; Pyrones; Receptor, ErbB-2; Receptors, Estrogen; Salvia miltiorrhiza