Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2009 Sep;64(4):829-35.
doi: 10.1007/s00280-009-0933-9. Epub 2009 Mar 3.

Carbonate and carbamate derivatives of 4-demethylpenclomedine as novel anticancer agents

Lee Roy Morgan  1 , Robert F Struck, William R Waud, Blaise LeBlanc, Andrew H Rodgers, Branko S Jursic
Affiliations

Carbonate and carbamate derivatives of 4-demethylpenclomedine as novel anticancer agents

Lee Roy Morgan et al. Cancer Chemother Pharmacol. 2009 Sep.

Abstract

Purpose: The purpose of this investigation was to synthesize a series of carbonate and carbamate derivatives of 4-demethylpenclomedine (DM-PEN), the major plasma non-toxic metabolite of penclomedine (PEN) seen in patients. DM-PEN has been observed to be an active antitumor agent in mouse human xenograft tumor models and non-neurotoxic in a rat model, however, activity in intracranially implanted human glioma xenograft models have not been reported. The major goal was to identify derivatives that are active in brain tumors.

Methods: Derivatives were prepared from DM-PEN and evaluated in vivo against human U251 glioblastoma, D54 glioblastoma and MX-1 breast tumor xenografts and mammary tumor 16/C that were implanted in the mammary fat pad or intracranially (IC).

Results: Carbonate and carbamate derivatives were found to be superior to DM-PEN against IC growing human glioblastoma xenografts.

Conclusion: The activity of the carbonates and carbamates against human tumor xenografts in vivo suggests consideration of these two series of derivatives of DM-PEN for clinical development.

PubMed Disclaimer

Figures

Fig. 1
Fig. 1
Where: PEN, R = CH3 and DM-PEN, R = H
Fig. 2
Fig. 2
Carbonate analogs synthesized (MS values)
Fig. 3
Fig. 3
Carbamate analogs synthesized (MS values)
Fig. 4
Fig. 4
Proposed mechanism of action of 4-demethyl-4-cholesterol-penclomedine (DM-CHOC-PEN)
See this image and copyright information in PMC

References

    1. {'text': '', 'ref_index': 1, 'ids': [{'type': 'PubMed', 'value': '9508201', 'is_inner': True, 'url': 'https://pubmed.ncbi.nlm.nih.gov/9508201/'}]}
    2. Berlin J, Stewart JA, Storer B, Tutsch KD, Arzoomanian RZ, Alberti D, Feierabend C, Simon K, Wilding G (1998) Phase I clinical and pharmacokinetic trial of penclomedine using a novel, two stage trial design for patients with advanced malignancy. J Clin Oncol 16:1142–1149 - PubMed
    1. {'text': '', 'ref_index': 1, 'ids': [{'type': 'PubMed', 'value': '9164209', 'is_inner': True, 'url': 'https://pubmed.ncbi.nlm.nih.gov/9164209/'}]}
    2. O’Reilly S, Grochow L, Donehower RC, Bowling K, Chen TL, Hartman N, Struck R, Rowinsky EK (1997) Phase I and pharmacologic studies of penclomedine, a novel alkylating agent in patients with solid tumors. J Clin Oncol 15:1974–1984 - PubMed
    1. {'text': '', 'ref_index': 1, 'ids': [{'type': 'PMC', 'value': 'PMC2149952', 'is_inner': False, 'url': 'https://pmc.ncbi.nlm.nih.gov/articles/PMC2149952/'}, {'type': 'PubMed', 'value': '9514062', 'is_inner': True, 'url': 'https://pubmed.ncbi.nlm.nih.gov/9514062/'}]}
    2. Jodrell DI, Bowman A, Stewart M, Dunlop N, French R, MacLellan A, Cummings J, Smyth JF (1998) Dose-limiting neurotoxicity in a phase I study of penclomedine (NSC 388720, CRC 88-04), a synthetic alpha-picoline derivative, administered intravenously. Br J Cancer 77:808–811 - PMC - PubMed
    1. None
    2. Berlin J, Wahamaki A, Tutsch KD, Alberti D, Feierabend C, Binger K, Arzoomanian RZ, Volkman J, Karca J, Mornocha R, Stewart J, Wilding G (1999) Phase I, pharmacokinetic and bioavailability study of oral penclomedine administered daily × 5 every four weeks. Proc Am Assoc Cancer Res 40:92
    1. {'text': '', 'ref_index': 1, 'ids': [{'type': 'PubMed', 'value': '9816256', 'is_inner': True, 'url': 'https://pubmed.ncbi.nlm.nih.gov/9816256/'}]}
    2. Hartman NR, O’Reilly S, Rowinsky EK, Collins JM, Strong JM (1996) Murine and human in vivo penclomedine metabolism. Clin Cancer Res 2:953–962 - PubMed

Publication types

LinkOut - more resources