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Targeting the plasma membrane of neoplastic cells through alkylation: a novel approach to cancer chemotherapy.

Trendowski M, Fondy TP - Invest New Drugs (2015)

Bottom Line: Plasma membrane alkylating agents have elicited long term survival in mammalian models challenged with carcinomas, sarcomas, and leukemias.Further, a specialized group of plasma membrane alkylating agents known as tetra-O-acetate haloacetamido carbohydrate analogs (Tet-OAHCs) potentiates a substantial leukocyte influx at the administration and primary tumor site, indicative of a potent immune response.The effects of plasma membrane alkylating agents may be further potentiated through the use of another novel class of chemotherapeutic agents, known as dihydroxyacetone phosphate (DHAP) inhibitors, since many cancer types are known to rely on the DHAP pathway for lipid synthesis.

View Article: PubMed Central - PubMed

Affiliation: Department of Biology, Syracuse University, 107 College Place, Syracuse, NY, 13244, USA, mrtrendo@syr.edu.

ABSTRACT

Background: Although DNA-directed alkylating agents and related compounds have been a mainstay in chemotherapeutic protocols due to their ability to readily interfere with the rapid mitotic progression of malignant cells, their clinical utility is limited by DNA repair mechanisms and immunosuppression. However, the same destructive nature of alkylation can be reciprocated at the cell surface using novel plasma membrane alkylating agents.

Results: Plasma membrane alkylating agents have elicited long term survival in mammalian models challenged with carcinomas, sarcomas, and leukemias. Further, a specialized group of plasma membrane alkylating agents known as tetra-O-acetate haloacetamido carbohydrate analogs (Tet-OAHCs) potentiates a substantial leukocyte influx at the administration and primary tumor site, indicative of a potent immune response. The effects of plasma membrane alkylating agents may be further potentiated through the use of another novel class of chemotherapeutic agents, known as dihydroxyacetone phosphate (DHAP) inhibitors, since many cancer types are known to rely on the DHAP pathway for lipid synthesis.

Conclusion: Despite these compelling data, preliminary clinical trials for plasma membrane-directed agents have yet to be considered. Therefore, this review is intended for academics and clinicians to postulate a novel approach of chemotherapy; altering critical malignant cell signaling at the plasma membrane surface through alkylation, thereby inducing irreversible changes to functions needed for cell survival.

No MeSH data available.


Related in: MedlinePlus

Characterization of haloacetamide structure. a General structure of haloacetamides. The highly reactive halogen (X) is ideal for an alkylation reaction. Such compounds are known to react by SN2 mechanisms, enabling a concerted reaction to occur in hydrophobic environments, such as the plasma membrane. Reactivity at the CH2X group is controlled by the electron withdrawing or donating power of the R group, and the corresponding pKa of the parent amine. The hydrogen bond donating and accepting properties of the amide nitrogen allow the reactivity to be modulated by the dielectric constant of the in vivo environment. b Basic structure of haloacetamido carbohydrates. C) Synthesis of tetra-O-acetylated D-mannose analogs. A different set of reactions are needed to make the fluoro derivative compared to the bromo and chloro derivatives. Mannose analogs were devised since 2-deoxy-2-acetamido-D-mannose is a metabolic precursor for sialic acid, a vital component of cell-surface biochemistry. Panels A and B were adapted from [21]. The scheme for D-mannose analogs was adapted from [18]
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Fig1: Characterization of haloacetamide structure. a General structure of haloacetamides. The highly reactive halogen (X) is ideal for an alkylation reaction. Such compounds are known to react by SN2 mechanisms, enabling a concerted reaction to occur in hydrophobic environments, such as the plasma membrane. Reactivity at the CH2X group is controlled by the electron withdrawing or donating power of the R group, and the corresponding pKa of the parent amine. The hydrogen bond donating and accepting properties of the amide nitrogen allow the reactivity to be modulated by the dielectric constant of the in vivo environment. b Basic structure of haloacetamido carbohydrates. C) Synthesis of tetra-O-acetylated D-mannose analogs. A different set of reactions are needed to make the fluoro derivative compared to the bromo and chloro derivatives. Mannose analogs were devised since 2-deoxy-2-acetamido-D-mannose is a metabolic precursor for sialic acid, a vital component of cell-surface biochemistry. Panels A and B were adapted from [21]. The scheme for D-mannose analogs was adapted from [18]

Mentions: Critical analysis of effective halo compounds in vivo has revealed such agents are able to partition from an aqueous to hydrophobic environment (amphiphilic log P value), and have a marked propensity to act as SN2 alkylators that react with strong electron donors [21]. By contrast, related compounds that are only strong alkylators, or amphiphilic do not potentiate the same antitumor activity [16–18]. Further, active haloacetamide compounds often have additional electron withdrawing groups which greatly increase alkylation potential. The pKa of the parent amine from which active haloacetamide compounds are made correlates well with the alkylating activity of the antitumor agents, as is expected; the more acidic the pKa, the more reactive the derived α-haloacetamide should be. In fact, their reactivity at the CH2X group is controlled by the electron withdrawing or donating power of the R-group, and the corresponding pKa of the parent amine (Fig. 1a). This also happens to be the case with nitrogen mustards which have long been used in the clinical setting due to their alkylating potential. However, haloacetamides have apparent hydrogen bond donating and accepting properties due to the presence of the amide nitrogen, indicating that compounds can be designed to have their activity modulated by the dielectric constant of the in vivo environment [21]. That localization could in turn be readily controlled by the lipid: water partition coefficient of the given haloacetamide. Further, nitrogen mustards react by SN1 mechanisms [22], which are not partial to hydrophobic environments; ideal for alkylating hydrophilic DNA, but not the hydrophobic environment of the plasma membrane. Due to the SN2 mechanisms observed in haloacetamides, the compounds react with electron donors even in nonpolar environments, allowing alkylation of functional groups on the surface of the plasma membrane to be a feasible prospect.Fig. 1


Targeting the plasma membrane of neoplastic cells through alkylation: a novel approach to cancer chemotherapy.

Trendowski M, Fondy TP - Invest New Drugs (2015)

Characterization of haloacetamide structure. a General structure of haloacetamides. The highly reactive halogen (X) is ideal for an alkylation reaction. Such compounds are known to react by SN2 mechanisms, enabling a concerted reaction to occur in hydrophobic environments, such as the plasma membrane. Reactivity at the CH2X group is controlled by the electron withdrawing or donating power of the R group, and the corresponding pKa of the parent amine. The hydrogen bond donating and accepting properties of the amide nitrogen allow the reactivity to be modulated by the dielectric constant of the in vivo environment. b Basic structure of haloacetamido carbohydrates. C) Synthesis of tetra-O-acetylated D-mannose analogs. A different set of reactions are needed to make the fluoro derivative compared to the bromo and chloro derivatives. Mannose analogs were devised since 2-deoxy-2-acetamido-D-mannose is a metabolic precursor for sialic acid, a vital component of cell-surface biochemistry. Panels A and B were adapted from [21]. The scheme for D-mannose analogs was adapted from [18]
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4491345&req=5

Fig1: Characterization of haloacetamide structure. a General structure of haloacetamides. The highly reactive halogen (X) is ideal for an alkylation reaction. Such compounds are known to react by SN2 mechanisms, enabling a concerted reaction to occur in hydrophobic environments, such as the plasma membrane. Reactivity at the CH2X group is controlled by the electron withdrawing or donating power of the R group, and the corresponding pKa of the parent amine. The hydrogen bond donating and accepting properties of the amide nitrogen allow the reactivity to be modulated by the dielectric constant of the in vivo environment. b Basic structure of haloacetamido carbohydrates. C) Synthesis of tetra-O-acetylated D-mannose analogs. A different set of reactions are needed to make the fluoro derivative compared to the bromo and chloro derivatives. Mannose analogs were devised since 2-deoxy-2-acetamido-D-mannose is a metabolic precursor for sialic acid, a vital component of cell-surface biochemistry. Panels A and B were adapted from [21]. The scheme for D-mannose analogs was adapted from [18]
Mentions: Critical analysis of effective halo compounds in vivo has revealed such agents are able to partition from an aqueous to hydrophobic environment (amphiphilic log P value), and have a marked propensity to act as SN2 alkylators that react with strong electron donors [21]. By contrast, related compounds that are only strong alkylators, or amphiphilic do not potentiate the same antitumor activity [16–18]. Further, active haloacetamide compounds often have additional electron withdrawing groups which greatly increase alkylation potential. The pKa of the parent amine from which active haloacetamide compounds are made correlates well with the alkylating activity of the antitumor agents, as is expected; the more acidic the pKa, the more reactive the derived α-haloacetamide should be. In fact, their reactivity at the CH2X group is controlled by the electron withdrawing or donating power of the R-group, and the corresponding pKa of the parent amine (Fig. 1a). This also happens to be the case with nitrogen mustards which have long been used in the clinical setting due to their alkylating potential. However, haloacetamides have apparent hydrogen bond donating and accepting properties due to the presence of the amide nitrogen, indicating that compounds can be designed to have their activity modulated by the dielectric constant of the in vivo environment [21]. That localization could in turn be readily controlled by the lipid: water partition coefficient of the given haloacetamide. Further, nitrogen mustards react by SN1 mechanisms [22], which are not partial to hydrophobic environments; ideal for alkylating hydrophilic DNA, but not the hydrophobic environment of the plasma membrane. Due to the SN2 mechanisms observed in haloacetamides, the compounds react with electron donors even in nonpolar environments, allowing alkylation of functional groups on the surface of the plasma membrane to be a feasible prospect.Fig. 1

Bottom Line: Plasma membrane alkylating agents have elicited long term survival in mammalian models challenged with carcinomas, sarcomas, and leukemias.Further, a specialized group of plasma membrane alkylating agents known as tetra-O-acetate haloacetamido carbohydrate analogs (Tet-OAHCs) potentiates a substantial leukocyte influx at the administration and primary tumor site, indicative of a potent immune response.The effects of plasma membrane alkylating agents may be further potentiated through the use of another novel class of chemotherapeutic agents, known as dihydroxyacetone phosphate (DHAP) inhibitors, since many cancer types are known to rely on the DHAP pathway for lipid synthesis.

View Article: PubMed Central - PubMed

Affiliation: Department of Biology, Syracuse University, 107 College Place, Syracuse, NY, 13244, USA, mrtrendo@syr.edu.

ABSTRACT

Background: Although DNA-directed alkylating agents and related compounds have been a mainstay in chemotherapeutic protocols due to their ability to readily interfere with the rapid mitotic progression of malignant cells, their clinical utility is limited by DNA repair mechanisms and immunosuppression. However, the same destructive nature of alkylation can be reciprocated at the cell surface using novel plasma membrane alkylating agents.

Results: Plasma membrane alkylating agents have elicited long term survival in mammalian models challenged with carcinomas, sarcomas, and leukemias. Further, a specialized group of plasma membrane alkylating agents known as tetra-O-acetate haloacetamido carbohydrate analogs (Tet-OAHCs) potentiates a substantial leukocyte influx at the administration and primary tumor site, indicative of a potent immune response. The effects of plasma membrane alkylating agents may be further potentiated through the use of another novel class of chemotherapeutic agents, known as dihydroxyacetone phosphate (DHAP) inhibitors, since many cancer types are known to rely on the DHAP pathway for lipid synthesis.

Conclusion: Despite these compelling data, preliminary clinical trials for plasma membrane-directed agents have yet to be considered. Therefore, this review is intended for academics and clinicians to postulate a novel approach of chemotherapy; altering critical malignant cell signaling at the plasma membrane surface through alkylation, thereby inducing irreversible changes to functions needed for cell survival.

No MeSH data available.


Related in: MedlinePlus