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2 edition of Molecular and cellular pharmacology of rationally designed PBD dimers found in the catalog.

Molecular and cellular pharmacology of rationally designed PBD dimers

Melissa Smellie

Molecular and cellular pharmacology of rationally designed PBD dimers

by Melissa Smellie

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Published by University of Portsmouth in Portsmouth .
Written in English


Edition Notes

Statementby Melissa Smellie.
ID Numbers
Open LibraryOL21288801M

  PBD dimers are a recently discovered class of potent cytotoxic agents that are thought to initiate cellular damage through DNA cross-linking that eventually leads to apoptosis and cell death. 19,20 Consistent with this presumed mechanism, SGN-CD33A or SGD induced significant increases in the levels of phosphorylated H2AX, an early DNA.   The pyrrolo[2,1‐c][1,4]benzodiazepines (PBDs) are a family of sequence‐selective DNA minor‐groove binding agents that form a covalent aminal bond between their C11‐position and the C2‐NH 2 groups of guanine bases. The first example of a PBD monomer, the natural product anthramycin, was discovered in the s, and the best known PBD dimer, SJG‐ (also known as SG, NSC .

Antibody–drug conjugates (ADCs) represent an important class of emerging cancer therapeutics. Recent ADC development efforts highlighted the use of pyrrolobenzodiazepine (PBD) dimer payload for the treatment of several cancers. We identified the isoquinolidinobenzodiazepine (IQB) payload (D), a new class of PBD dimer family of DNA damaging payloads.   Plasma concentrations of SJG associated with pharmacological activity and in vitro antiproliferative activity were achieved with doses that were tolerated by rats. CYP3A isoforms are the predominant Ps catalyzing SJG metabolism. The comet assay detects DNA damage in PBMCs from rats treated with SJG and is being used in clinical trials to monitor in vivo lesions produced .

  As an alternative to the delivery of tubulin binding-based warheads, novel ADCs delivering highly cytotoxic pyrrolobenzodiazepine (PBD) dimers have been developed. PBD dimers are a class of exquisitely potent DNA minor groove interstrand crosslinking agents 16 ; one of which, SG (SJG) has shown activity against both solid tumor and hematological malignancies. 17,18 . Small molecules continue to dominate drug discovery because of their ease of use, lower cost of manufacturing, and access to intracellular targets. However, despite these advantages, small molecules are more likely to fail in clinical trials compared with biologicals and their development remains limited to a small subset of disease-relevant ‘druggable’ targets.


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Molecular and cellular pharmacology of rationally designed PBD dimers by Melissa Smellie Download PDF EPUB FB2

Molecular and cellular pharmacology of rationally designed PBD dimers. (Thesis) Smellie M. Publisher: University of Portsmouth [] Metadata Source: The British Library Type: Thesis. Abstract. No abstract supplied. Menu.

Formats. Abstract Author: Smellie M. Molecular and cellular pharmacology of rationally designed PBD dimers. Author: Smellie, Melissa. ISNI: Awarding Body: University of Portsmouth Current Institution: University of Portsmouth Date of Award: Availability of Full Text.

SJG (NSC ), a novel rationally designed DNA minor groove interstrand cross-linking agent with potent and broad spectrum antitumour activity: Part 1: Cellular pharmacology Cited by: SJG (NSC ) is a rationally designed pyrrolobenzodiazepine dimer that binds in the minor groove of DNA. It spans 6 bp with a preference for binding to purine-GATC-pyrimidine sequences.

Synthetically produced PBD dimers exhibit potent cytotoxicity by crosslinking DNA strands, and a PBD dimer, SG (Figure 2c), could inhibit the growth of various human cancer cell.

Prodrug 9a was established to be non-toxic in the human adenocarcinoma cell-line LST (IC 50 => μM), whereas in the presence of nitroreductase and NADH co-factor the IC 50 was found to be between and μM (Fig.

2 and Table 1), suggesting an activation factor of ∼fold or appears to represent only partial release of the parent C8-O-benzyl-DC (), as an.

SJG (NSC ), a novel rationally designed DNA minor groove interstrand cross-linking agent with potent and broad spectrum antitumor activity: part 1: cellular pharmacology, invitro and initial invivo antitumor activity.

Cancer Res ; – 9. A number of cytotoxic pyrrolobenzodiazepine (PBD) monomers containing various disulfide-based prodrugs were evaluated for their ability to undergo activation (disulfide cleavage) in vitro in the presence of either glutathione (GSH) or cysteine (Cys).

A good correlation was observed between in vitro GSH stability and in vitro cytotoxicity toward tumor cell lines. The prodrug-containing. Pyrrolobenzodiazepine dimers are an emerging class of warhead in the field of antibody–drug conjugates (ADCs). Tesirine (SG) was designed to combine potent antitumor activity with desirable physicochemical properties such as favorable hydrophobicity and improved conjugation characteristics.

One of the reactive imines was capped with a cathepsin B-cleavable valine-alanine. Pyrrolobenzodiazepine (PBD) derivatives are highly potent sequence-specific DNA cross-linking agents. The present study aimed to identify key physicochemical properties influencing the interaction of a series of PBDs (four dimers and 12 monomers) with the three major human ATP-binding cassette (ABC) transporters (P-gp, ABCG2, and MRP1).

Isogenic cell lines expressing P-gp and ABCG2, cell. INTRODUCTION. Pyrrolobenzodiazepine (PBD) dimers [e.g. 1–3, Figure 1] are synthetic sequence-selective DNA-interactive agents based on the naturally occurring anthramycin family of antitumour antibiotics (e.g.

the PBD monomers anthramycin and tomaymycin, Figure 1) that target the minor groove of DNA (1–3).The PBD dimers contain two C8-linked PBD monomer units, both of which contain an. Hartley JA, et al. SJG (NSC ), a novel rationally designed DNA minor groove interstrand cross-linking agent with potent and broad spectrum antitumour activity: Part 1: Cellular pharmacology, in vitro and initial in vivo antitumour activity.

Cancer Res. Three rationally designed pyrrolobenzodiazepine (PBD) drug-linkers have been synthesized via intermediate 19 for use in antibody-drug conjugates (ADCs). They lack a cleavable trigger in the linker and consist of a maleimide for cysteine antibody conjugation, a hydrophilic spacer, and either an alkyne (6), triazole (7), or piperazine (8) link to.

INTRODUCTION. Pyrrolobenzodiazepine (PBD) dimers [e.g. 1–3, Figure 1] are synthetic sequence-selective DNA-interactive agents based on the naturally occurring anthramycin family of antitumour antibiotics (e.g.

the PBD monomers anthramycin and tomaymycin, Figure 1) that target the minor groove of DNA ().The PBD dimers contain two C8-linked PBD monomer units, both of which contain an.

ADCs delivering PBD dimer payloads represent a novel mode of action in the ADC area. An important feature of the highly cytotoxic DNA interstrand cross-links produced by the PBD dimers is their persistence in cells.

This contributes to their potency and also to their ability to affect slowly proliferating target cells, including cancer stem cells. Sibiromycin is the most potent naturally occurring PBD (IC 50 L, leukaemia = nM).

12 It contains an amino sugar derivative at the C7 position and a trans-propenyl group at the C2 position that interacts favourably with the minor groove of have previously synthesized a sibiromycin-like PBD di SG, a more potent cytotoxic agent than stand-alone clinical.

Here we sought to evaluate the contribution of the PBD unit to the biological activity of PBD-conjugates and, to this end, an adenosine nucleoside was attached to the PBD A-ring C8 position. A convergent approach was successfully adopted for the synthesis of a novel C8-linked pyrrolo(2,1-c)(1,4)benzodiazepine(PBD)-adenosine(ADN) hybrid.

The PBD and adenosine (ADN) moieties were. Pyrrolobenzodiazepine dimers (PBD) form cross-links within the minor groove of DNA causing double-strand breaks (DSB). DNA repair genes such as BRCA1 and BRCA2 play important roles in homologous recombination repair of DSB.

We hypothesized that PBD-based antibody–drug conjugates (ADC) will have enhanced killing of cells in which homologous recombination processes are defective by. Title: SJG (NSC ), a novel rationally designed DNA minor groove interstrand cross-linking agent with potent and broad spectrum antitumor activity: part 1: cellular pharmacology, in vitro and initial in vivo antitumor activity.

Journal: Cancer research Molecular pharmacology of G protein-coupled receptors in the Bräuner-Osborne group. The Bräuner-Osborne group focus on pharmacological and physiological characterization of G protein-coupled receptors bridging from development of novel pharmacological tool compounds by integration of pharmacology, medicinal chemistry and computer modeling to understand the physiological role and.

ecules were designed and synthesized, which were unsaturated at the C2/C2 positions (13) in an attempt to produce lower electrophilicity at the NC11 positions within the molecule to decrease deactivation by cellular nucleophiles (14).

A resulting C2-exo-methylene PBD dimer, SJG (Fig. 1), was found to be significantly more cytotoxic. Hartley, J.

A. et al. SJG (NSC ), a novel rationally designed DNA minor groove interstrand cross-linking agent with potent and broad spectrum antitumor activity: part 1: Cellular.SJG (NSC ) is a rationally designed pyrrolobenzodiazepine dimer that binds in the minor groove of DNA. It spans 6 bp with a preference for binding to purine-GATC-pyrimidine sequences.

The agent has potent activity in the National Cancer Institute (NCI) anticancer drug screen with 50% net growth inhibition conferred by to nmol/L ( nmol/L mean).