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

Morgan LR, Struck RF, Waud WR, LeBlanc B, Rodgers AH, Jursic BS - Cancer Chemother. Pharmacol. (2009)

Bottom Line: 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.The major goal was to identify derivatives that are active in brain tumors.Carbonate and carbamate derivatives were found to be superior to DM-PEN against IC growing human glioblastoma xenografts.

View Article: PubMed Central - PubMed

Affiliation: DEKK-TEC Inc, New Orleans, LA, USA. lrm1579@aol.com

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.

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Related in: MedlinePlus

Proposed mechanism of action of 4-demethyl-4-cholesterol-penclomedine (DM-CHOC-PEN)
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Fig4: Proposed mechanism of action of 4-demethyl-4-cholesterol-penclomedine (DM-CHOC-PEN)

Mentions: A non-classical carbonium ion alkylating mechanism is proposed for DM-CHOC-PEN’s anticancer activities in Fig. 4. The scheme describes a dual free radical/carbonium ion DNA cross-linking mechanism with tumor DNA in the major groove via N7-guanine resulting in a G-X-C cross-linking sequence [14]. A bimolecular coupled product (via the trichloromethylene group) has been identified as the major microsomal metabolite of PEN [10, 14]. The trichloromethylene group is thought to be needed, since a dichloromethylene analog of PEN is not active [does not react with 4-(p-nitrobenzyl)pyridine (NBP)] (Struck, personnel communication). No other modifications of the moiety have been studied.Fig. 4


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

Morgan LR, Struck RF, Waud WR, LeBlanc B, Rodgers AH, Jursic BS - Cancer Chemother. Pharmacol. (2009)

Proposed mechanism of action of 4-demethyl-4-cholesterol-penclomedine (DM-CHOC-PEN)
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2717391&req=5

Fig4: Proposed mechanism of action of 4-demethyl-4-cholesterol-penclomedine (DM-CHOC-PEN)
Mentions: A non-classical carbonium ion alkylating mechanism is proposed for DM-CHOC-PEN’s anticancer activities in Fig. 4. The scheme describes a dual free radical/carbonium ion DNA cross-linking mechanism with tumor DNA in the major groove via N7-guanine resulting in a G-X-C cross-linking sequence [14]. A bimolecular coupled product (via the trichloromethylene group) has been identified as the major microsomal metabolite of PEN [10, 14]. The trichloromethylene group is thought to be needed, since a dichloromethylene analog of PEN is not active [does not react with 4-(p-nitrobenzyl)pyridine (NBP)] (Struck, personnel communication). No other modifications of the moiety have been studied.Fig. 4

Bottom Line: 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.The major goal was to identify derivatives that are active in brain tumors.Carbonate and carbamate derivatives were found to be superior to DM-PEN against IC growing human glioblastoma xenografts.

View Article: PubMed Central - PubMed

Affiliation: DEKK-TEC Inc, New Orleans, LA, USA. lrm1579@aol.com

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.

Show MeSH
Related in: MedlinePlus