Antitumor Agents. 272. Structure−Activity Relationships and In Vivo Selective Anti-Breast Cancer Activity of Novel Neo-tanshinlactone Analogues

Abstract

Neo-tanshinlactone (1) and its previously reported analogs, such as 2, are potent and selective in vitro anti-breast 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 anti-breast agents. Several derivatives (19-21 and 24) exerted potent and selective anti-breast cancer activity with IC 50 values of 0.3, 0.2, 0.1 and 0.1 μg/ mL, respectively, against the ZR-75-1 cell lines. Compound 24 was two-to three-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, analog 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.

Discovery of new anticancer agents from higher plants

“…Unlike the tanshinones, neo-tanshinlactone ( 39 ) possesses a lactone feature rather than an ortho -quinone moiety in ring C. This compound exhibited selectivity against two estrogen receptor-positive (ER + ) breast cancer cell lines, MCF-7 and ZR-75-1, with ED 50 values, in turn, of 0.6 and 0.3 μg/mL (111). Compound 40 , a synthetic analogue of neo-tanshinlactone ( 39 ), was found to inhibit the growth of the estrogen-dependent breast cancer cells, ZR-75-1, in an in vivo xenograft model (112). These investigations suggest that neo-tanshinlactone ( 39 ) and its derivatives might be promising candidates for the treatment of hormone-dependent breast cancers.…”

Antitumor Agents. 289. Design, Synthesis, and Anti-Breast Cancer Activity in Vivo of 4-Amino-2H-benzo[h]chromen-2-one and 4-Amino-7,8,9,10-tetrahydro-2H-benzo[h]chromen-2-one Analogues with Improved Water Solubility

“…11 Cell lines included KB (nasopharyngeal carcinoma), KB-vin (vincristine-resistant MDR KB subline), A549 (non-small-cell lung cancer), DU145 (prostate cancer cell line), and SK-BR-3 (estrogen receptor negative, HER2 over-expressing breast cancer).…”

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

“…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…”

“…Structure-activity relationship (SAR) studies on 3 and 4 indicated that (1) a secondary amine (R 2 or R 3 = H) is preferred over tertiary amine (R 2 and R 3 ≠ H), (2) bulky groups are favored at the R 2 /R 3 position, (3) a 3′-bromophenyl group can cause a dramatic loss of potency, and (4) a non-aromatic ring-A can increase potency and cancer cell line selectivity for certain analogs. Our studies also indicated that the lactone ring-C is critical to the cytotoxic activity 3,7,8. Therefore, we designed a structurally simplified monocyclic scaffold ( 5 , Figure 1) and incorporated various substituents at the R and R′ positions to explore the contributions of ring-A and -B, develop new chemical entities and new leads, and establish the SAR.…”

“…3 Cell lines included A549 (non small cell lung cancer), DU145 (prostate cancer cell line), KB (nasopharyngeal carcinoma), and KB-VIN (vincristine-resistant MDR KB subline), SK-BR-3 (estrogen receptor negative, HER2 over-expressing breast cancer). Importantly, 13 showed significant inhibition of all human cancer cell lines tested with ED 50 values from 1.23–2.02 μM, while 12 displayed moderate activity.…”