Synthesis and in Vitro Evaluation of Quaternary Ammonium Derivatives of Chlorambucil and Melphalan, Anticancer Drugs Designed for the Chemotherapy of Chondrosarcoma

Giraud, Isabelle; Rapp, Maryse; Maurizis, Jean‐Claude; Madelmont, Jean‐Claude

doi:10.1021/jm010926x

Cited by 47 publications

(30 citation statements)

References 11 publications

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“…Quaternary ammonium derivatives have also been reported to show enhanced antitumor activity compared with their parent compounds (Giraud et al, 2002), suggesting that molecules possessing quaternary ammonium moieties may be highly effective anticancer agents.…”

mentioning

confidence: 99%

Potential Use of Cetrimonium Bromide as an Apoptosis-Promoting Anticancer Agent for Head and Neck Cancer

Ito

Yip²,

Katz³

et al. 2009

Mol Pharmacol

118

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A potential therapeutic agent for human head and neck cancer (HNC), cetrimonium bromide (CTAB), was identified through a cell-based phenotype-driven high-throughput screen (HTS) of 2000 biologically active or clinically used compounds, followed by in vitro and in vivo characterization of its antitumor efficacy. The preliminary and secondary screens were performed on FaDu (hypopharyngeal squamous cancer) and GM05757 (primary normal fibroblasts), respectively. Potential hit compounds were further evaluated for their anticancer specificity and efficacy in combination with standard therapeutics on a panel of normal and cancer cell lines. Mechanism of action, in vivo antitumor efficacy, and potential lead compound optimizations were also investigated. In vitro, CTAB interacted additively with ␥ radiation and cisplatin, two standard HNC therapeutic agents.CTAB exhibited anticancer cytotoxicity against several HNC cell lines, with minimal effects on normal fibroblasts; a selectivity that exploits cancer-specific metabolic aberrations. The central mode of cytotoxicity was mitochondria-mediated apoptosis via inhibition of H ϩ -ATP synthase activity and mitochondrial membrane potential depolarization, which in turn was associated with reduced intracellular ATP levels, caspase activation, elevated sub-G 1 cell population, and chromatin condensation. In vivo, CTAB ablated tumor-forming capacity of FaDu cells and delayed growth of established tumors. Thus, using an HTS approach, CTAB was identified as a potential apoptogenic quaternary ammonium compound possessing in vitro and in vivo efficacy against HNC models.

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mentioning

confidence: 99%

Potential Use of Cetrimonium Bromide as an Apoptosis-Promoting Anticancer Agent for Head and Neck Cancer

Ito

Yip²,

Katz³

et al. 2009

Mol Pharmacol

118

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“…The quaternary ammonium-melphalan conjugate was prepared as previously described [14], following the four-step scheme illustrated in Scheme 1. First, melphalan was treated by di-tert-butyl dicarbonate with Et 3 N in methanol to protect the amine function.…”

Section: Chemistrymentioning

confidence: 99%

Quaternary ammonium-melphalan conjugate for anticancer therapy of chondrosarcoma: in vitro and in vivo preclinical studies

et al. 2011

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Cartilage tumours present ongoing therapeutic challenges due to their chondrogenic extracellular matrix that potentially hampers drug delivery, their low percentage of dividing cells, and their poor vascularity. In this context, and based on the affinity of the quaternary ammonium moiety for proteoglycans (PG), we developed a strategy that uses the quaternary ammonium function to selectively deliver DNA alkylating agents to the cartilage tumour tissue. We engineered the quaternary ammonium derivative of melphalan (Mel-AQ) and assessed its antitumoural activity in vitro and in vivo. In vitro, micromolar concentrations of Mel-AQ inhibited the proliferation of human HEMC-SS chondrosarcoma and Saos-2 osteosarcoma cell lines. Moreover, 24-h incubation with 20 μM Mel-AQ induced a 2.5-fold increase in S population and a 1.5-fold increase in subG0G1 population compared to controls. In vivo, Mel-AQ demonstrated antitumour activity in the orthotopic model of primary Swarm rat chondrosarcoma. When given to chondrosarcoma-bearing rats (three doses of 16 μmol/kg at days 8, 12 and 16 post-implant), Mel-AQ demonstrated an optimal antitumour effect at day 43, when tumour cell growth inhibition peaked at 69%. Interestingly, the treatment protocol was proved well tolerated, since the animals showed no weight loss over the course of the study. This antitumoural effect was assessed in vivo by scintigraphic imaging using (99m)Tc-NTP 15-5 developed in our lab as a PG-targeting radiotracer, and tumour tissue was analyzed at study-end by biochemical PG assay with Alcian blue staining. Mel-AQ treatment led to a significant decrease in the PG content of tumoural tissue. These experimental results highlighted the promising antitumour potential of Mel-AQ as a PG-targeting strategy for therapeutic management of chondrosarcoma.

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“…In order to target cartilage professor Madelmont and coworkers synthesized quaternary ammonium derivatives of chlorambucil and melphalan (Fig. 3D), showing unchanged cytotoxic activity in vitro and in vivo biodisposition to cartilage [62,63], proof-of-concept in vivo are awaited. Fig.…”

Section: Incorporation Into Peptide Receptor Ligandsmentioning

confidence: 99%

Future Prospects for Old Chemotherapeutic Drugs in the Target-Specific Era; Pharmaceutics, Combinations, Co-Drugs and Prodrugs with Melphalan as an Example

Wickström¹,

Lövborg²,

Gullbo³

2006

LDDD

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During the last decade, resulting from expanded knowledge in tumor biology, several new and target-specific approaches have been presented. With some exceptions, however, most early clinical trials with these compounds are discouraging, suggesting that the expanding knowledge might not easily translate into new substantially better anti-cancer drugs. One of the classical chemotherapeutic agents is melphalan, first synthesized over fifty years ago. The anti-tumor effect has been attributed to alkylation of cellular nucleophiles, among them DNA. Intravenous melphalan has single-agent activity in a variety of solid tumors and has good activity alone or combined with other drugs or radiation in high-dose bone marrow transplant regimens for breast cancer, ovarian cancer, testicular cancer and multiple myeloma. Recent studies suggest a continuous role for melphalan as part of high dose combination therapy in advanced solid tumor malignancies. Immediately after the first publication on melphalan (p-L-bis(2-chloroethyl)aminophenylalanine), investigators began attempting to improve the therapeutic index and thus provide a greater margin of clinical safety during treatment with the drug. The amino-acid based chemical structure of melphalan invites to modification of both the N-and C-termini as well as incorporation into peptides.In this review we discuss the past and present history of melphalan in the perspective of modern cancer chemotherapy, from the medicinal chemist's point of view, and with special emphasis on how target-directed approaches have been applied to the molecule.

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Synthesis and in Vitro Evaluation of Quaternary Ammonium Derivatives of Chlorambucil and Melphalan, Anticancer Drugs Designed for the Chemotherapy of Chondrosarcoma

Cited by 47 publications

References 11 publications

Potential Use of Cetrimonium Bromide as an Apoptosis-Promoting Anticancer Agent for Head and Neck Cancer

Potential Use of Cetrimonium Bromide as an Apoptosis-Promoting Anticancer Agent for Head and Neck Cancer

Quaternary ammonium-melphalan conjugate for anticancer therapy of chondrosarcoma: in vitro and in vivo preclinical studies

Future Prospects for Old Chemotherapeutic Drugs in the Target-Specific Era; Pharmaceutics, Combinations, Co-Drugs and Prodrugs with Melphalan as an Example

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