Synthesis of a COMC–estradiol conjugate for targeted, tissue-selective cancer chemotherapy

Oaksmith, Jennifer M.; Ganem, Bruce

doi:10.1016/j.tetlet.2009.03.083

Cited by 8 publications

(5 citation statements)

References 19 publications

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“…Further, as the ER is overexpressed in 50–80% of all breast cancers, it represents an ideal target for receptor‐mediated drug delivery. Some of the earliest examples of targeted delivery mediated by the ER was to conjugate the β‐Estradiol, or estrogen analogs (tamoxifen), to the following cytotoxic molecules: porphyrins, enediynes, Taxol, mitomycin C, nitrosourea, geldanamycin, mustine, ellipticine, chlorambucil, and 2‐crotonyloxymethyl‐(4R,5R,6R)‐4,5,6‐trihydroxy‐2‐cyclohexenone . However, the ER‐binding affinities of these conjugates was compromised due to the modification of the hormone.…”

Section: Receptors Targets For Inhibiting Metastasismentioning

confidence: 99%

Advances in Receptor‐Mediated, Tumor‐Targeted Drug Delivery

Large

Soucy

Hebert

et al. 2018

Advanced Therapeutics

129

101

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Receptor-mediated drug delivery presents an opportunity to enhance therapeutic efficiency by accumulating drug within the tissue of interest and reducing undesired, off-target effects. In cancer, receptor overexpression is a platform for binding and inhibiting pathways that shape biodistribution, toxicity, cell binding and uptake, and therapeutic function. This review will identify tumor-targeted drug delivery vehicles and receptors that show promise for clinical translation based on quantitative in vitro and in vivo data. The authors describe the rationale to engineer a targeted drug delivery vehicle based on the ligand, chemical conjugation method, and type of drug delivery vehicle. Recent advances in multivalent targeting and ligand organization on tumor accumulation are discussed. Revolutionizing receptor-mediated drug delivery may be leveraged in the therapeutic delivery of chemotherapy, gene editing tools, and epigenetic drugs.in the site of interest. This is clinically important as reaching a therapeutic dosage locally and reducing systemic toxicity can be life-threatening or life-saving events for cancer patients.The design of targeted DDVs can be optimized by altering the size, shape, material, ligand, and ligand orientation. For systemic delivery, spherical DDVs less than 200 nm in diameter are standard, which is balanced by the trade off between surface area and volume ratio. DDVs are prepared from biomaterials based on the size, hydrophobicity, and ideal release of the drug. There are a diverse range of ligand candidates for DDV functionalization, including monoclonal antibodies (mAbs), peptides, oligosaccharides, small molecules, and aptamers. [5] These ligands can be tethered to vehicles or conjugated directly to drugs by covalent (typically thiol or amide-based reactions, or "click" chemistry) or noncovalent attachment; the type of reaction is often based on the material of the DDV. [6] Multi-targeted and patterned DDVs improved cancer cell binding and the overall therapeutic benefit in vivo. The ideal DDV platform may be rationally designed by evaluating the drug, release mechanism, mode of delivery into the body, and target cells.Utilizing these approaches, targeted DDVs were successfully translated from the research setting into clinical use, or are currently in preclinical trials. [7] Liposomal based DDVs were approved for use in cancer therapy, treating fungal diseases, analgesics, photodynamic therapy, and viral vaccines. [8] Specifically, FDA approved liposomal drug formulations, such as Mepact, Maribo, and Epaxal were proven to be effective for the treatment of nonmetastatic osteosarcoma, acute lymphoblastic leukemia, and hepatitis A, respectively. [9] Many targeted DDVs in clinical use are utilized for the treatment of multiple cancer types, as there is often broad overlap in malignant receptor overexpression across various carcinogenic tissues (Figure 1). The widely successful drug Pembrolizumab (Keytruda), a humanized IgG4 isotype mAb that targets the programmed cell death (PD-1) rec...

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Section: Receptors Targets For Inhibiting Metastasismentioning

confidence: 99%

Advances in Receptor‐Mediated, Tumor‐Targeted Drug Delivery

Large

Soucy

Hebert

et al. 2018

Advanced Therapeutics

129

101

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“…1 H NMR (400 MHz, CDCl 3 ) δ 2.44 (s, 3H), 3.83 (s, 3H), 6.90 (d, 2H, J = 8.9 Hz); 7.33 (s, 1H), 7.47 (d, J = 8.9 Hz, 2H), 7.66À7.76 (m, 2H), 8.13À8.25 (m, 2H); 13 C NMR (100 MHz, CDCl 3 ) δ 21.0, 55. 3 4-Amino-3-[(1,5-dimethyl-1H-pyrazol-4-yl)ethynyl]-9,10dioxo-9,10-dihydroanthracen-1-yl Acetate 6e. Typical Procedure for the Preparation of Substituted Azides 3aÀd…”

Section: -(M-toluidinomentioning

confidence: 99%

“…Synthetic transformations of plant metabolites constitute an important direction of medicinal chemistry . Since hybrid molecules that combine two structural units of different nature lend themselves well to rational structural design and often possess high biological activity, a number of hybrids are described in the literature such as steroid–antibiotic, steroid–nucleoside, triterpenoid–peptide, DNA-cleaving agent–amino acid, etc. In this work, we report a successful approach to bioconjugates that combine acetylenic derivatives known to have anticancer activity and condensed anthraquinoid cycles, capable of intercalating DNA duplex …”

Section: Introductionmentioning

confidence: 99%

Chameleonic Reactivity of Vicinal Diazonium Salt of Acetylenyl-9,10-anthraquinones: Synthetic Application toward Two Heterocyclic Targets

Степанов

Gornostaev

Vasilevsky³

et al. 2011

J. Org. Chem.

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The nature of products in the diazotization of 1-amino-2-acetylenyl-9,10-anthraquinones strongly depends on the nature of substituents at both the alkyne and at the anthraquinone core. Donor substitution (NHAr, OH) at the fourth position stabilizes the diazonium salt at C1, decelerating electrophilic cyclization at the arylethynyl substituent at C2. This effect allows the replacement of the diazonium with azide group and subsequent closure into isoxazole ring with preservation of the alkyne. In contrast, electrophilic 5-exo-dig cyclizations to condensed pyrazoles is observed for the combination of donor substituents at the aryl alkyne moiety and an OAc substituent at C4. The latter process provides a new synthetic route to 3-ethynyl-[1,9-cd]isoxazol-6-ones that are difficult to access otherwise. DFT calculations suggest that donor substituents have only a minor effect on alkyne and diazonium polarization in the reactant but provide specific transition state stabilization by stabilizing the incipient vinyl cation. This analysis provides the first computational data on electrophilic 5-exo-dig cyclization in its parent form and the nucleophile-promoted version. This cyclization is a relatively fast but endothermic process that is rendered thermodynamically feasible by the enol-keto tautomerization with concomitant aromatization in the five-membered heteroaromatic ring. Computations suggest that the importance of nucleophilic assistance in the transition state for a relatively weak nucleophile such as water is minor because the energy gain due to the Lewis base coordination to the carbocationic center is more than compensated for by the unfavorable entropic term for the bimolecular proces.

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“…Up until now steroids have showed potential applications as 5α-reductase inhibitors [ 13 ], as modulators of inflammation and immunity [ 14 ], as inhibitors of 17α-hydroxylase/C 17,20 -lyase [ 15 ], as predictor of tamoxifen response in premenopausal breast cancer [ 16 ], as progesterone receptor antagonist [ 17 ], as glucocorticoid receptor imaging agents [ 18 ], as inhibitors of protein tyrosine phosphatase 1B [ 19 ], as reversal agents of multidrug resistance in cancer cells [ 20 ], as inhibitors of 17β-hydroxysteroid dehydrogenase [ 21 ], and as ligands for drug vectors [ 22 ]. Some steroidal compounds were used for photodynamic therapy [ 23 ], for cancer chemotherapy [ 24 ], and for DNA delivery [ 25 ]. Moreover, cholesteric liquid crystal [ 26 ] and steroid-based organogelator [ 27 ] were also studied.…”

Section: Introductionmentioning

confidence: 99%

Synthesis and characterization of new aromatic esters based on 4,16-pregnadiene-6,20-dione skeleton

2010

Chemistry Central Journal

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A series of new aromatic esters based on 4,16-pregnadiene-6,20-dione skeleton, namely 3β-benzoyloxy-4,16-pregnadiene-6,20-dione and 3β-furoyloxy-4,16-pregnadiene- 6,20-dione, which may be good inhibitors for the 5α-reductase enzyme and show high antiandrogenic activity, were synthesized starting from diosgenin. The structures of the steroids were characterized by elemental analysis, 1H NMR, 13C NMR, IR and mass spectrum. Single crystal X-ray diffraction measurement on one of the new compounds, 3β-(p-methoxybenzoyloxy)-4,16-pregnadiene-6,20-dione revealed that the A, B, C, and D ring adopted half chair, distorted chair, distorted chair, and distorted envelope conformation, respectively. The molecules in the crystal were packed face-to-face at the normal van der Waals distances.

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Synthesis of a COMC–estradiol conjugate for targeted, tissue-selective cancer chemotherapy

Cited by 8 publications

References 19 publications

Advances in Receptor‐Mediated, Tumor‐Targeted Drug Delivery

Advances in Receptor‐Mediated, Tumor‐Targeted Drug Delivery

Chameleonic Reactivity of Vicinal Diazonium Salt of Acetylenyl-9,10-anthraquinones: Synthetic Application toward Two Heterocyclic Targets

Synthesis and characterization of new aromatic esters based on 4,16-pregnadiene-6,20-dione skeleton

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