Novel Selective Estrogen Receptor Ligand Conjugates Incorporating Endoxifen-Combretastatin and Cyclofenil-Combretastatin Hybrid Scaffolds: Synthesis and Biochemical Evaluation

Abstract

Nuclear receptors such as the estrogen receptors (ERα and ERβ) modulate the effects of the estrogen hormones and are important targets for design of innovative chemotherapeutic agents for diseases such as breast cancer and osteoporosis. Conjugate and bifunctional compounds which incorporate an ER ligand offer a useful method of delivering cytotoxic drugs to tissue sites such as breast cancers which express ERs. A series of novel conjugate molecules incorporating both the ER ligands endoxifen and cyclofenil-endoxifen hybrids covalently linked to the antimitotic and tubulin targeting agent combretastatin A-4 were synthesised and evaluated as ER ligands. A number of these compounds demonstrated pro-apoptotic effects, with potent antiproliferative activity in ER-positive MCF-7 breast cancer cell lines and low cytotoxicity. These conjugates displayed binding affinity towards ERα and ERβ isoforms at nanomolar concentrations e.g., the cyclofenil-amide compound 13e is a promising lead compound of a clinically relevant ER conjugate with IC50 in MCF-7 cells of 187 nM, and binding affinity to ERα (IC50 = 19 nM) and ERβ (IC50 = 229 nM) while the endoxifen conjugate 16b demonstrates antiproliferative activity in MCF-7 cells (IC50 = 5.7 nM) and binding affinity to ERα (IC50 = 15 nM) and ERβ (IC50 = 115 nM). The ER binding effects are rationalised in a molecular modelling study in which the disruption of the ER helix-12 in the presence of compounds 11e, 13e and 16b is presented These conjugate compounds have potential application for further development as antineoplastic agents in the treatment of ER positive breast cancers.

Monocrotaline Suppresses RANKL-Induced Osteoclastogenesis In Vitro and Prevents LPS-Induced Bone Loss In Vivo

“…The major modalities currently used in these diseases treatment, including bisphosphonates [30], selective estrogen receptor modulators (SERM) [31], and denosumab (a RANKL Inhibitor) [32]. However, these therapies are associated with side effects, including renal toxicity and osteonecrosis [33], endometrial cancer risk [34], and osteonecrosis of the jaws [35].…”

Drug conjugates—an emerging approach to treat breast cancer

“…Additionally, this conjugate displayed high affinity toward the estrogen receptor α and was superior to cisplatin in inducing tumor regression in the MCF‐7 human breast cancer tumors in a mouse model. Recently, conjugates of selective estrogen receptor modulators (ie, endoxifen or cyclofenil) linked to combretastatin, an antimitotic agent that binds to the beta subunit of tubulin, demonstrated potent (nmol/L) antiproliferative activity against MCF‐7 cells (Table ) …”

“…Recently, conjugates of selective estrogen receptor modulators (ie, endoxifen or cyclofenil) linked to combretastatin, an antimitotic agent that binds to the beta subunit of tubulin, demonstrated potent (nmol/L) antiproliferative activity against MCF-7 cells (Table 4). 56,58 An estrogen receptor antagonist, oxabicycloheptene sulfonate, linked to the histone deacetylase (HDAC) inhibitor vorinostat (suberanilohydroxamic acid) showed higher antitumor potency in MCF-7 cells compared to the oxabicycloheptene sulfonate alone, indicating that parallel inhibition of HDAC and the estrogen receptor is beneficial for anticancer action. 107 DNA-alkylating agents linked to estrogen receptor ligands is yet another approach to developing novel hybrid drugs targeting specific phenotypes of breast cancer.…”

Microwave-assisted efficient one-pot synthesis of N 2-(tetrazol-5-yl)-6-aryl/heteroaryl-2,3-dihydro-1,3,5-triazine-2,4-diamines

“…It is well established that many medical disorders can be caused as a result of defects in more than one specific biological target as receptor or enzyme. A promising strategy overcomes the classical one-target, one-molecule approach is the design of stable chemical hybrid molecules which are combination of two biologically active scaffolds acting at different targets [21][22][23][24][25]. Accordingly, we reasoned that heterocycles incorporating both N 2 -(tetrazol-5-yl) ring system and 1,3,5-triazine-2,4-diamine scaffold could be very effective biologically relevant heterocycles.…”