Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 7 de 7
Filter
1.
Bioorg Med Chem Lett ; 30(7): 126987, 2020 04 01.
Article in English | MEDLINE | ID: mdl-32029324

ABSTRACT

Pyrrolobenzodiazepines (PBDs) and their dimers (bis-PBDs) have emerged as some of the most potent chemotherapeutic compounds and are currently under development as novel payloads in antibody-drug conjugates (ADCs). However, when used as stand-alone therapeutics or as warheads for small molecule drug conjugates (SMDCs), dose-limiting toxicities are often observed. As an elegant solution to this inherent problem, we designed and synthesized a diazepine-ring-opened bis-PBD prodrug (pro-PBD-PBD) folate conjugate lacking the one of the two imine moieties found in the corresponding free bis-PBD. Upon entering a targeted cell, cleavage of the linker system, including the hydrolysis of an oxazolidine moiety, results in the formation of a reactive intermediate which possesses a newly formed aldehyde as well as an aromatic amine. A fast and spontaneous intramolecular ring-closing reaction subsequently takes place as the aromatic amine adds to the aldehyde with the loss of water to give the imine, and as a result, the diazepine ring, thereby delivering the bis-PBD to the targeted cell. The in vitro and in vivo activity of this conjugate has been evaluated on folate receptor positive KB cells. Sub-nanomolar activity with good specificity and high cure rates with minimal toxicity have been observed.


Subject(s)
Antibiotics, Antineoplastic/therapeutic use , Benzodiazepines/therapeutic use , Folate Receptors, GPI-Anchored/metabolism , Neoplasms/drug therapy , Prodrugs/therapeutic use , Pyrroles/therapeutic use , Animals , Antibiotics, Antineoplastic/chemical synthesis , Antibiotics, Antineoplastic/pharmacology , Benzodiazepines/chemical synthesis , Benzodiazepines/pharmacology , Drug Design , Female , HeLa Cells , Humans , Mice, Nude , Prodrugs/chemical synthesis , Prodrugs/pharmacology , Pyrroles/chemical synthesis , Pyrroles/pharmacology , Xenograft Model Antitumor Assays
2.
Mol Pharm ; 16(9): 3985-3995, 2019 09 03.
Article in English | MEDLINE | ID: mdl-31356752

ABSTRACT

Folate-based small molecule drug conjugates (SMDCs) are currently under development and have shown promising preclinical and clinical results against various cancers and polycystic kidney disease. Two requisites for response to a folate-based SMDC are (i) folate receptor alpha (FRα) protein is expressed in the diseased tissues, and (ii) FRα in those tissues is accessible and functionally competent to bind systemically administered SMDCs. Here we report on the development of a small molecule reporter conjugate (SMRC), called EC2220, which is composed of a folate ligand for FRα binding, a multilysine containing linker that can cross-link to FRα in the presence of formaldehyde fixation, and a small hapten (fluorescein) used for immunohistochemical detection. Data show that EC2220 produces a far greater IHC signal in FRα-positive tissues over that produced with EC17, a folate-fluorescein SMRC that is released from the formaldehyde-denatured FRα protein. Furthermore, the extent of the EC2220 IHC signal was proportional to the level of FRα expression. This EC2220-based assay was qualified both in vitro and in vivo using normal tissue, cancer tissue, and polycystic kidneys. Overall, EC2220 is a sensitive and effective reagent for evaluating functional and accessible receptor expression in vitro and in vivo.


Subject(s)
Folate Receptor 1/metabolism , Molecular Targeted Therapy/methods , Neoplasms/drug therapy , Polycystic Kidney Diseases/drug therapy , A549 Cells , Animals , Doxycycline/pharmacology , Fluorescein-5-isothiocyanate/chemistry , Fluorescein-5-isothiocyanate/metabolism , Folate Receptor 1/analysis , Folic Acid/analogs & derivatives , Folic Acid/chemistry , Folic Acid/metabolism , HeLa Cells , Humans , Lysine/analogs & derivatives , Lysine/chemistry , Lysine/metabolism , Mice , Mice, Inbred BALB C , Mice, Nude , Mice, Transgenic , Neoplasms/metabolism , Oligopeptides/chemistry , Oligopeptides/metabolism , Polycystic Kidney Diseases/chemically induced , Polycystic Kidney Diseases/metabolism , Protein Kinase C/genetics , Tissue Distribution , Trityl Compounds/chemistry , Trityl Compounds/metabolism , Xenograft Model Antitumor Assays
3.
Bioconjug Chem ; 28(12): 2921-2931, 2017 Dec 20.
Article in English | MEDLINE | ID: mdl-29211454

ABSTRACT

Pyrrolobenzodiazepines (PBDs) and their dimers (bis-PBDs) have emerged as some of the most potent chemotherapeutic compounds, and are currently under development as novel payloads in antibody-drug conjugates (ADCs). However, when used as stand-alone therapeutics or as warheads for small molecule drug conjugates (SMDCs), dose-limiting toxicities are often observed. As an elegant solution to this inherent problem, we designed diazepine-ring-opened conjugated prodrugs lacking the imine moiety. Once the prodrug (pro-PBD) conjugate enters a targeted cell, cleavage of the linker system triggers the generation of a reactive intermediate possessing an aldehyde and aromatic amine. An intramolecular ring-closing reaction subsequently takes place as the aromatic amine adds to the aldehyde with the loss of water to give the imine and, as a result, the diazepine ring. In our pro-PBDs, we mask the aldehyde as a hydrolytically sensitive oxazolidine moiety which in turn is a part of a reductively labile self-immolative linker system. To prove the range of applications for this new class of latent DNA-alkylators, we designed and synthesized several novel latent warheads: pro-PBD dimers and hybrids of pro-PBD with other sequence-selective DNA minor groove binders. Preliminary preclinical pharmacology studies showed excellent biological activity and specificity.


Subject(s)
Benzodiazepines/chemistry , Benzodiazepines/metabolism , Drug Design , Molecular Targeted Therapy , Neoplasms/drug therapy , Prodrugs/chemical synthesis , Prodrugs/metabolism , Pyrroles/chemistry , Pyrroles/metabolism , Antineoplastic Agents/chemistry , Antineoplastic Agents/metabolism , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Benzodiazepines/pharmacology , Benzodiazepines/therapeutic use , Chemistry Techniques, Synthetic , Humans , KB Cells , Neoplasms/pathology , Prodrugs/chemistry , Pyrroles/pharmacology , Pyrroles/therapeutic use
4.
J Nucl Med ; 65(1): 100-108, 2024 Jan 02.
Article in English | MEDLINE | ID: mdl-38050111

ABSTRACT

The overexpression of fibroblast activation protein-α (FAP) in solid cancers relative to levels in normal tissues has led to its recognition as a target for delivering agents directly to tumors. Radiolabeled quinoline-based FAP ligands have established clinical feasibility for tumor imaging, but their therapeutic potential is limited due to suboptimal tumor retention, which has prompted the search for alternative pharmacophores. One such pharmacophore is the boronic acid derivative N-(pyridine-4-carbonyl)-d-Ala-boroPro, a potent and selective FAP inhibitor (FAPI). In this study, the diagnostic and therapeutic (theranostic) potential of N-(pyridine-4-carbonyl)-d-Ala-boroPro-based metal-chelating DOTA-FAPIs was evaluated. Methods: Three DOTA-FAPIs, PNT6555, PNT6952, and PNT6522, were synthesized and characterized with respect to potency and selectivity toward soluble and cell membrane FAP; cellular uptake of the Lu-chelated analogs; biodistribution and pharmacokinetics in mice xenografted with human embryonic kidney cell-derived tumors expressing mouse FAP; the diagnostic potential of 68Ga-chelated DOTA-FAPIs by direct organ assay and small-animal PET; the antitumor activity of 177Lu-, 225Ac-, or 161Tb-chelated analogs using human embryonic kidney cell-derived tumors expressing mouse FAP; and the tumor-selective delivery of 177Lu-chelated DOTA-FAPIs via direct organ assay and SPECT. Results: DOTA-FAPIs and their natGa and natLu chelates exhibited potent inhibition of human and mouse sources of FAP and greatly reduced activity toward closely related prolyl endopeptidase and dipeptidyl peptidase 4. 68Ga-PNT6555 and 68Ga-PNT6952 showed rapid renal clearance and continuous accumulation in tumors, resulting in tumor-selective exposure at 60 min after administration. 177Lu-PNT6555 was distinguished from 177Lu-PNT6952 and 177Lu-PNT6522 by significantly higher tumor accumulation over 168 h. In therapeutic studies, all 3 177Lu-DOTA-FAPIs exhibited significant antitumor activity at well-tolerated doses, with 177Lu-PNT6555 producing the greatest tumor growth delay and animal survival. 225Ac-PNT6555 and 161Tb-PNT6555 were similarly efficacious, producing 80% and 100% survival at optimal doses, respectively. Conclusion: PNT6555 has potential for clinical translation as a theranostic agent in FAP-positive cancer.


Subject(s)
Gallium Radioisotopes , Positron-Emission Tomography , Humans , Animals , Mice , Tissue Distribution , Cell Line, Tumor , Pyridines
5.
J Org Chem ; 78(18): 9471-6, 2013 Sep 20.
Article in English | MEDLINE | ID: mdl-23952564

ABSTRACT

The enantioselective synthesis of substituted pyrrolidines through a mild Lewis-acid catalyzed three-component coupling reaction between picolinaldehyde, amino acids, and activated olefins is reported. The reaction uses low catalyst loadings of commercially available chiral diamines and copper triflate proposed to self-assemble in conjunction with the chelating aldehydes, 4-substituted-2-picolinaldehydes or 4-methylthiazole-2-carboxaldehyde, to generate a catalyst complex. A model is provided to explain how this complex directs enantioselectivity. This work represents a significant advance in the ease, scope, and cost of producing highly substituted, enantioenriched pyrrolidines.


Subject(s)
Alkenes/chemistry , Amino Acids/chemistry , Pyridines/chemistry , Pyrrolidines/chemical synthesis , Models, Molecular , Molecular Structure , Pyrrolidines/chemistry , Stereoisomerism
6.
Sci Rep ; 10(1): 12772, 2020 07 29.
Article in English | MEDLINE | ID: mdl-32728172

ABSTRACT

Folate receptor (FR)-targeted small molecule drug conjugates (SMDCs) have shown promising results in early stage clinical trials with microtubule destabilizing agents, such as vintafolide and EC1456. In our effort to develop FR-targeted SMDCs with varying mechanisms of action, we synthesized EC2629, a folate conjugate of a DNA crosslinking agent based on a novel DNA-alkylating moiety. This agent was found to be extremely potent with an in vitro IC50 ~ 100× lower than folate SMDCs constructed with various microtubule inhibitors. EC2629 treatment of nude mice bearing FR-positive KB human xenografts led to cures in 100% of the test animals with very low dose levels (300 nmol/kg) following a convenient once a week schedule. The observed activity was not accompanied by any noticeable weight loss (up to 20 weeks post end of dosing). Complete responses were also observed against FR-positive paclitaxel (KB-PR) and cisplatin (KB-CR) resistant models. When evaluated against FR-positive patient derived xenograft (PDX) models of ovarian (ST070), endometrial (ST040) and triple negative breast cancers (ST502, ST738), EC2629 showed significantly greater anti-tumor activity compared to their corresponding standard of care treatments. Taken together, these studies thus demonstrated that EC2629, with its distinct DNA reacting mechanism, may be useful in treating FR-positive tumors, including those that are classified as drug resistant.


Subject(s)
Antineoplastic Agents/pharmacology , Cross-Linking Reagents/pharmacology , DNA/chemistry , Endometrial Neoplasms/drug therapy , Folate Receptors, GPI-Anchored/chemistry , Ovarian Neoplasms/drug therapy , Triple Negative Breast Neoplasms/drug therapy , Alkylating Agents/chemistry , Animals , Cattle , Cisplatin/administration & dosage , Dogs , Drug Delivery Systems , Drug Design , Drug Evaluation, Preclinical , Female , Folic Acid/analogs & derivatives , Folic Acid/pharmacology , Humans , Inhibitory Concentration 50 , KB Cells , Ligands , Mice , Mice, Inbred C57BL , Mice, Nude , Paclitaxel/administration & dosage , Rats , Vinca Alkaloids/pharmacology , Xenograft Model Antitumor Assays
7.
Org Lett ; 12(9): 1916-9, 2010 May 07.
Article in English | MEDLINE | ID: mdl-20364829

ABSTRACT

Metal complexes of picolinaldehyde are identified as low-cost and environmentally benign catalysts, providing high reaction rates and turnovers for the racemization of amino acids. These pyridoxal surrogates demonstrate activity toward a variety of amino acid esters. Applications to chemoenzymatic dynamic kinetic resolutions provide access to amino acids in high yields and with excellent enantioselectivities, demonstrating their compatibility with protease-mediated transformations.


Subject(s)
Amino Acids/chemistry , Pyridoxal/chemistry , Kinetics
SELECTION OF CITATIONS
SEARCH DETAIL