The Experts below are selected from a list of 234 Experts worldwide ranked by ideXlab platform
Norman E Sladek - One of the best experts on this subject based on the ideXlab platform.
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Leukemic cell insensitivity to cyclophosphamide and other Oxazaphosphorines mediated by aldehyde dehydrogenase(s).
Cancer treatment and research, 2002Co-Authors: Norman E SladekAbstract:“Acquired” insensitivity to cyclophosphamide and therOxazaphosphorines, e.g., 4-ydroperoxycyclophosphamide (4HC), mafosfamide, ifosfamide and 4-hydroperoxyifosfamide, on the part of the leukemias for which these agents are used is encountered all too often clinically. Increased detoxification of the Oxazaphosphorines catalyzed by relatively elevated levels of any of several aldehyde dehydrogenases (ALDHs) present in target (malignant) cells could, at least in some cases, account for the relative insensitivity to these agents. Presently, however, there is no direct evidence (as would be provided by a prospective study, or even retrospective analysis, comparing [1] therapeutic responses to therapeutic strategies of which an Oxazaphosphorine is a part with [2] cellular levels of relevant ALDH activity) to support that notion. By the same token, there is little direct evidence disputing it. Herein summarized is the indirect evidence consistent, as well as inconsistent, with the aforementioned possibility
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Aldehyde dehydrogenase-mediated cellular relative insensitivity to the Oxazaphosphorines.
Current pharmaceutical design, 1999Co-Authors: Norman E SladekAbstract:As judged by findings in preclinical models, determinants of cellular sensitivity to cyclophosphamide and other Oxazaphosphorines include two cytosolic aldehyde dehydrogenases, viz., ALDH1A1 and ALDH3A1. Each catalyzes the detoxification of the Oxazaphosphorines; thus, cellular sensitivity to these agents decreases as cellular levels of ALDH1A1 and/or ALDH3A1 increase. Of particular clinical relevance may be that stable sublines, relatively insensitive to the Oxazaphosphorines due to elevated ALDH1A1 or ALDH3A1 levels, emerged when cultured human tumor cells were exposed only once to a high concentration of one of these agents for 30 to 60 minutes. Whether differences in cellular levels of either enzyme accounts for the clinically-encountered uneven therapeutic effectiveness of the Oxazaphosphorines remains to be determined. However, it has already been established that measurable levels of these enzymes are found in some, but not all, tumor types, and that in those tumor types where measurable levels are present, e.g., infiltrating ductal carcinomas of the breast, they vary widely from patient to patient. Potentially useful clinical strategies that might be pursued if it turns out that ALDH1A1 and/or ALDH3A1 are, indeed, clinically operative determinants of cellular sensitivity to the Oxazaphosphorines include 1) individualizing cancer chemotherapeutic regimens based, at least in part, on the levels of these enzymes in the malignancy of interest, and 2) sensitizing tumor cells that express relatively large amounts of ALDH1A1 and/or ALDH3A1 to the Oxazaphosphorines by preventing the synthesis of these enzymes, e.g., with antisense RNA, or by introducing an agent that directly inhibits the catalytic action of the operative enzyme. Further, the fact that ALDH1A1 and ALDH3A1 are determinants of cellular sensitivity to the Oxazaphosphorines provides the rationale for the investigation of two additional strategies with clinical potential, viz., decreasing the sensitivity of vulnerable and essential normal cells, e.g., pluripotent hematopoietic cells, to the Oxazaphosphorines by selectively transferring into them the genetic information that encodes 1) ALDH1A1 or ALDH3A1, or 2) a signaling factor, the presence of which would directly or indirectly, stably upregulate the expression of these enzymes.
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Inhibition of Human Class 3 Aldehyde Dehydrogenase, and Sensitization of Tumor Cells that Express Significant Amounts of this Enzyme to Oxazaphosphorines, by the Naturally Occurring Compound Gossypol
Advances in experimental medicine and biology, 1997Co-Authors: Ganaganur K. Rekha, Norman E SladekAbstract:Cytosolic class 3 aldehyde dehydrogenase (ALDH-3) is a demonstrated determinant of cellular sensitivity to the cytotoxic action of certain widely used antineoplastic prodrugs collectively referred to as Oxazaphosphorines, e.g., cyclophosphamide, ifosfamide, 4-hydroperoxycyclophosphamide, 4-hydroperoxyifosfamide and mafosfamide (cellular sensitivity to these drugs decreases as cellular levels of ALDH-3 increase) (Sladek, 1993; Sreerama and Sladek, 1993a,b, 1994; Bunting et al., 1994; Rekha et al., 1994; Sladek et al., 1995; Sreerama et al., 1995; Bunting and Townsend, 1996). Thus, tumor cells, otherwise sensitive to the Oxazaphosphorines, became resistant to these drugs when electroporated with purified ALDH-3 protein or transfected with the cDNA coding for ALDH-3 (Bunting et al., 1994; Sreerama and Sladek, 1995; Bunting and Townsend, 1996), and, of therapeutic significance, relatively elevated levels of this enzyme can account for intrinsic, transient acquired, and stable acquired, resistance to the Oxazaphosphorines on the part of malignant cells (Sreerama and Sladek, 1993a,b, 1994; Rekha et al., 1994; Sreerama et al., 1995). Resistance to the Oxazaphosphorines mediated by ALDH-3 is ostensibly due to the enzyme-catalyzed oxidative detoxification of aldophosphamide, the pivotal metabolite of these prodrugs (Sreerama and Sladek, 1993a, 1994; Rekha et al., 1994; Sreerama et al., 1995; Bunting and Townsend, 1996).
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Breast Cancer Resistance to Cyclophosphamide and Other Oxazaphosphorines
1996Co-Authors: Norman E SladekAbstract:Abstract : Cyclophosphamide, mafosfamide and 4-hydroperoxycyclophosphamide are antineoplastic agents collectively referred to as Oxazaphosphorines. Each of these is a prodrug, i.e., per se, without cytotoxic activity. Salient features of the metabolic activation of Oxazaphosphorines are presented. Oxazaphosphorines are clinically effective; they play a lead role in the treatment of breast cancer until resistant subpopulations become the dominant population. An understanding of how resistance to these agents is effected would likely to be of value because measures may then become apparent as to how to reverse, and/or prevent, it. It is this understanding which is the overall objective of our first-generation investigations.
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Phenolic antioxidant-induced overexpression of class-3 aldehyde dehydrogenase and Oxazaphosphorine-specific resistance.
Biochemical pharmacology, 1995Co-Authors: Lakshmaiah Sreerama, Ganaganur K. Rekha, Norman E SladekAbstract:Abstract High-level cytosolic class-3 aldehyde dehydrogenase (ALDH-3)-mediated Oxazaphosphorine-specific resistance (> 35-fold as judged by the concentrations of mafosfamide required to effect a 90% cell-kill) was induced in cultured human breast adenocarcinoma MCF-7/0 cells by growing them in the presence of 30 μM catechol for 5 days. Resistance was transient in that cellular sensitivity to mafosfamide was fully restored after only a few days when the inducing agent was removed from the culture medium. The operative enzyme was identified as a type-1 ALDH-3. Cellular levels of glutathione S -transferase and DT-diaphorase activities, but not of cytochrome P450 IA1 activity, were also elevated. Other phenolic antioxidants, e.g. hydroquinone and 2,6-di- tert -butyl-4-hydroxytoluene, also induced ALDH- 3 activity when MCF-7/0 cells were cultured in their presence. Thus, the increased expression of a type-1 ALDH-3 and the other enzymes induced by these agents was most probably the result of transcriptional activation of the relevant genes via antioxidant responsive elements present in their 5′-flanking regions. Cellular levels of ALDH-3 activity were also increased when a number of other human tumor cell lines, e.g. breast adenocarcinoma MDA-MB-231, breast carcinoma T-47D and colon carcinoma HCT 116b, were cultured in the presence of catechol. These findings should be viewed as greatly expanding the number of recognized environmental and dietary agents that can potentially negatively influence the sensitivity of tumor cells to cyclophosphamide and other Oxazaphosphorines.
Lakshmaiah Sreerama - One of the best experts on this subject based on the ideXlab platform.
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Phenolic antioxidant-induced overexpression of class-3 aldehyde dehydrogenase and Oxazaphosphorine-specific resistance.
Biochemical pharmacology, 1995Co-Authors: Lakshmaiah Sreerama, Ganaganur K. Rekha, Norman E SladekAbstract:Abstract High-level cytosolic class-3 aldehyde dehydrogenase (ALDH-3)-mediated Oxazaphosphorine-specific resistance (> 35-fold as judged by the concentrations of mafosfamide required to effect a 90% cell-kill) was induced in cultured human breast adenocarcinoma MCF-7/0 cells by growing them in the presence of 30 μM catechol for 5 days. Resistance was transient in that cellular sensitivity to mafosfamide was fully restored after only a few days when the inducing agent was removed from the culture medium. The operative enzyme was identified as a type-1 ALDH-3. Cellular levels of glutathione S -transferase and DT-diaphorase activities, but not of cytochrome P450 IA1 activity, were also elevated. Other phenolic antioxidants, e.g. hydroquinone and 2,6-di- tert -butyl-4-hydroxytoluene, also induced ALDH- 3 activity when MCF-7/0 cells were cultured in their presence. Thus, the increased expression of a type-1 ALDH-3 and the other enzymes induced by these agents was most probably the result of transcriptional activation of the relevant genes via antioxidant responsive elements present in their 5′-flanking regions. Cellular levels of ALDH-3 activity were also increased when a number of other human tumor cell lines, e.g. breast adenocarcinoma MDA-MB-231, breast carcinoma T-47D and colon carcinoma HCT 116b, were cultured in the presence of catechol. These findings should be viewed as greatly expanding the number of recognized environmental and dietary agents that can potentially negatively influence the sensitivity of tumor cells to cyclophosphamide and other Oxazaphosphorines.
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identification of a methylcholanthrene induced aldehyde dehydrogenase in a human breast adenocarcinoma cell line exhibiting Oxazaphosphorine specific acquired resistance
Cancer Research, 1994Co-Authors: Lakshmaiah Sreerama, Norman E SladekAbstract:The class-3 aldehyde dehydrogenase that is overexpressed (>100-fold) in human breast adenocarcinoma MCF-7/0 cells made resistant (>30-fold as judged by LC90s) to Oxazaphosphorines, such as mafosfamide, by growing them in the presence of polycyclic aromatic hydrocarbons, e.g. , methylcholanthrene (3 µm for 5 days), was isolated and characterized. Its physical and catalytic properties were identical to those of the prototypical human stomach mucosa cytosolic class-3 aldehyde dehydrogenase, type-1 ALDH-3, except that it catalyzed, though not very rapidly, the oxidation of aldophosphamide, whereas the stomach mucosa enzyme essentially did not; hence, it was judged to be a slight variant of the prototypical enzyme. Carcinogens that are not ligands for the Ah receptor, barbiturates known to induce hepatic cytochrome P450s, steroid hormones, an antiestrogen, and Oxazaphosphorines did not induce the enzyme or the largely Oxazaphosphorine-specific acquired resistance. Whereas methylcholanthrene induced ( a ) resistance to mafosfamide and ( b ) class-3 aldehyde dehydrogenase activity, as well as glutathione S -transferase and DT-diaphorase activities, in the estrogen receptor-positive MCF-7/0 cells, it did not do so in two other human breast adenocarcinoma cell lines, MDA-MB-231 and SK-BR-3, each of which is estrogen receptor negative. Expression of the class-3 aldehyde dehydrogenase and the loss of sensitivity to mafosfamide by polycyclic aromatic hydrocarbon-treated MCF-7/0 cells were transient; each returned to essentially basal levels within 15 days when the polycyclic aromatic hydrocarbon was removed from the culture medium. Insensitivity to the Oxazaphosphorines on the part of polycyclic aromatic hydrocarbon-treated MCF-7/0 cells was not observed when exposure to mafosfamide (30 min) was in the presence of benzaldehyde or octanal, each a relatively good substrate for cytosolic class-3 aldehyde dehydrogenases, whereas it was retained when exposure to mafosfamide was in the presence of acetaldehyde, a relatively poor substrate for these enzymes. These observations demonstrate that ligands for the Ah receptor can induce a transient, largely Oxazaphosphorine-specific, acquired cellular resistance, and they are consistent with the notion that elevated levels of a cytosolic class-3 aldehyde dehydrogenase nearly identical to the prototypical type-1 class-3 aldehyde dehydrogenase expressed by human stomach mucosa account for the Ah receptor ligand-induced Oxazaphosphorine-specific acquired resistance, most probably by catalyzing the detoxification of aldophosphamide.
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Identification and characterization of a novel class 3 aldehyde dehydrogenase overexpressed in a human breast adenocarcinoma cell line exhibiting Oxazaphosphorine-specific acquired resistance.
Biochemical pharmacology, 1993Co-Authors: Lakshmaiah Sreerama, Norman E SladekAbstract:Abstract Associated with the Oxazaphosphorine-specific acquired resistance exhibited by a human breast adenocarcinoma subline growing in monolayer culture, viz. MCF-7/OAP, was the overexpression (> 100-fold as compared with the very small amount expressed in the Oxazaphosphorine-sensitive parent line) of a class 3 aldehyde dehydrogenase, viz. ALDH-3, judged to be so because it is a polymorphic enzyme (pI values ca. 6.0) present in the cytosol that is heat labile, is insensitive to inhibition by disulfiram (25 μM), much prefers benzaldehyde to acetaldehyde as a substrate and, at concentrations of 4 mM, prefers NADP to NAD as a cofactor. No other aldehyde dehydrogenases were found in these cells. As compared with those of the prototypical class 3 human ALDH-3, viz. constitutive human stomach mucosa ALDH-3, the physical and catalytic properties of the MCF-7/OAP enzyme differed somewhat with regard to pI values, native M r , subunit M r , recognition of the subunit by anti-stomach ALDH-3 IgY, pH stability, cofactor influence on catalytic activity, and the ability to catalyze, albeit poorly, the oxidation of an Oxazaphosphorine, viz. aldophosphamide. Hence, the MCF-7/OAP ALDH-3 was judged to be a novel class 3 aldehyde dehydrogenase. Small amounts of a seemingly identical enzyme are also present in normal pre- and post-menopausal breast tissue. None could be detected in human liver, kidney or placenta, suggesting that it may be a tissue-specific enzyme.
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Overexpression or Polycyclic Aromatic Hydrocarbon-Mediated Induction of an Apparently Novel Class 3 Aldehyde Dehydrogenase in Human Breast Adenocarcinoma Cells and its Relationship to Oxazaphosphorine-Specific Acquired Resistance
Advances in experimental medicine and biology, 1993Co-Authors: Lakshmaiah Sreerama, Norman E SladekAbstract:Oxazaphosphorines such as cyclophosphamide are widely used in the treatment of certain neoplasms (Sladek, 1988). Because they are, perse, without cytotoxic activity, their metabolism, Figure 1, has been the subject of intensive investigation. In the course of these investigations, it was established that certain aldehyde dehydrogenases catalyze the irreversible detoxification of the Oxazaphosphorines when they catalyze the oxidation of aldophosphamide to carboxyphosphamide. Class 1 aldehyde dehydrogenases, e.g., mouse AHD-2 and human ALDH-1, are particularly important in this regard (Manthey et al., 1990; Dockham et al., 1992). Other “aldehyde” dehydrogenases, e.g., human ALDH-2 and succinic semialdehyde dehydrogenase, also catalyze the reaction albeit less well as judged by Km values (Dockham et al., 1992). Still others, e.g., human ALDH-4, ALDH-5 and betaine aldehyde dehydrogenase, do not catalyze the reaction at all (Dockham et al., 1992). The pharmacological upshot is that a relative Oxazaphosphorine-insensitivity is conferred on those cells in which constitutive or induced expression of the relevant enzyme(s) occurs.
U. Niemeyer - One of the best experts on this subject based on the ideXlab platform.
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The Anhydrous Racemate of the Carcinostatic Agent Cyclophosphamide and the Bicyclic Degradation Product 1‐(2‐Chloroethyl)tetrahydro‐1H,5H‐1,3,2‐diazaphospholo[2,1‐b][1,3,2]Oxazaphosphorine 9‐Oxide
Acta Crystallographica Section C Crystal Structure Communications, 1996Co-Authors: Peter G. Jones, Jürgen Engel, Holger Thönnessen, Axel K. Fischer, I. Neda, Reinhard Schmutzler, Bernhard Kutscher, U. NiemeyerAbstract:Anhydrous racemic cyclophosphamide, [(±)-N,N-bis(2-chloroethyl)-tetrahydro-2H-1,3,2-oxazaphosphorin-2-amine 2-oxide C7H15Cl2N2O2P, (1)], displays a chair conformation with axial phosphoryl oxygen and close to planar geometry at the N atoms. The molecules are linked by N-H⋯O=P hydrogen bonds into chains. One chloroethyl side chain is extended, the other is gauche. The C—Cl bond lengths are Cl1-C5 1.789 (2) and Cl2-C7 1.791 (2) A. The bicyclic degradation product, 1-(2-chloroethyl)tetrahydro-1H,5H–1,3,2-diazaphospholo[2,1-b][1,3,2]Oxazaphosphorine 9-oxide, C7H14ClN2O2P, (2), is formed by intramolecular alkylation at the ring N atom of (1). The major change of bond length upon annelation is observed for P—N2, the ring P—N bond in (1), which is lengthened from 1.633 (2) to 1.6593 (14) A. The angle N1—P—N2, incorporated into the five-membered ring in (2), narrows from 105.84 (8) to 97.36 (7)°. The remaining chloroethyl side chain is gauche. The C—Cl bond length is 1.790 (2) A.
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the anhydrous racemate of the carcinostatic agent cyclophosphamide and the bicyclic degradation product 1 2 chloroethyl tetrahydro 1h 5h 1 3 2 diazaphospholo 2 1 b 1 3 2 Oxazaphosphorine 9 oxide
Acta Crystallographica Section C-crystal Structure Communications, 1996Co-Authors: Peter G. Jones, Jürgen Engel, Holger Thönnessen, I. Neda, Reinhard Schmutzler, Bernhard Kutscher, A Fischer, U. NiemeyerAbstract:Anhydrous racemic cyclophosphamide, [(±)-N,N-bis(2-chloroethyl)-tetrahydro-2H-1,3,2-oxazaphosphorin-2-amine 2-oxide C7H15Cl2N2O2P, (1)], displays a chair conformation with axial phosphoryl oxygen and close to planar geometry at the N atoms. The molecules are linked by N-H⋯O=P hydrogen bonds into chains. One chloroethyl side chain is extended, the other is gauche. The C—Cl bond lengths are Cl1-C5 1.789 (2) and Cl2-C7 1.791 (2) A. The bicyclic degradation product, 1-(2-chloroethyl)tetrahydro-1H,5H–1,3,2-diazaphospholo[2,1-b][1,3,2]Oxazaphosphorine 9-oxide, C7H14ClN2O2P, (2), is formed by intramolecular alkylation at the ring N atom of (1). The major change of bond length upon annelation is observed for P—N2, the ring P—N bond in (1), which is lengthened from 1.633 (2) to 1.6593 (14) A. The angle N1—P—N2, incorporated into the five-membered ring in (2), narrows from 105.84 (8) to 97.36 (7)°. The remaining chloroethyl side chain is gauche. The C—Cl bond length is 1.790 (2) A.
Brian A. Keay - One of the best experts on this subject based on the ideXlab platform.
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Development of P -stereogenic 2-phenyl-1,3,2-Oxazaphosphorine ligands and their unexpected sensitivity to oxidation
Tetrahedron: Asymmetry, 2009Co-Authors: Wendy Benoit, Masood Parvez, Brian A. KeayAbstract:P-Stereogenic Oxazaphosphorine compounds of the form 4 have not previously been reported as asymmetric ligands for metal-catalyzed reactions. In an effort to explore the behavior of such Oxazaphosphorine ligands, monomeric Oxazaphosphorine borane 9 and dimeric Oxazaphosphorine boranes 25 and 26 were synthesized as catalyst precursors. The absolute configuration of the phosphorus center contained in the Oxazaphosphorines was determined by X-ray crystallography. Rhodium-catalyzed hydrogenation of methyl 2-acetamidoacrylate using a dimerized spiro Oxazaphosphorine ligand was performed with up to 15% ee. The extreme sensitivity of the Oxazaphosphorine ligands toward oxidation prevented further optimization of the enantioselectivity.
Peter G. Jones - One of the best experts on this subject based on the ideXlab platform.
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The Anhydrous Racemate of the Carcinostatic Agent Cyclophosphamide and the Bicyclic Degradation Product 1‐(2‐Chloroethyl)tetrahydro‐1H,5H‐1,3,2‐diazaphospholo[2,1‐b][1,3,2]Oxazaphosphorine 9‐Oxide
Acta Crystallographica Section C Crystal Structure Communications, 1996Co-Authors: Peter G. Jones, Jürgen Engel, Holger Thönnessen, Axel K. Fischer, I. Neda, Reinhard Schmutzler, Bernhard Kutscher, U. NiemeyerAbstract:Anhydrous racemic cyclophosphamide, [(±)-N,N-bis(2-chloroethyl)-tetrahydro-2H-1,3,2-oxazaphosphorin-2-amine 2-oxide C7H15Cl2N2O2P, (1)], displays a chair conformation with axial phosphoryl oxygen and close to planar geometry at the N atoms. The molecules are linked by N-H⋯O=P hydrogen bonds into chains. One chloroethyl side chain is extended, the other is gauche. The C—Cl bond lengths are Cl1-C5 1.789 (2) and Cl2-C7 1.791 (2) A. The bicyclic degradation product, 1-(2-chloroethyl)tetrahydro-1H,5H–1,3,2-diazaphospholo[2,1-b][1,3,2]Oxazaphosphorine 9-oxide, C7H14ClN2O2P, (2), is formed by intramolecular alkylation at the ring N atom of (1). The major change of bond length upon annelation is observed for P—N2, the ring P—N bond in (1), which is lengthened from 1.633 (2) to 1.6593 (14) A. The angle N1—P—N2, incorporated into the five-membered ring in (2), narrows from 105.84 (8) to 97.36 (7)°. The remaining chloroethyl side chain is gauche. The C—Cl bond length is 1.790 (2) A.
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the anhydrous racemate of the carcinostatic agent cyclophosphamide and the bicyclic degradation product 1 2 chloroethyl tetrahydro 1h 5h 1 3 2 diazaphospholo 2 1 b 1 3 2 Oxazaphosphorine 9 oxide
Acta Crystallographica Section C-crystal Structure Communications, 1996Co-Authors: Peter G. Jones, Jürgen Engel, Holger Thönnessen, I. Neda, Reinhard Schmutzler, Bernhard Kutscher, A Fischer, U. NiemeyerAbstract:Anhydrous racemic cyclophosphamide, [(±)-N,N-bis(2-chloroethyl)-tetrahydro-2H-1,3,2-oxazaphosphorin-2-amine 2-oxide C7H15Cl2N2O2P, (1)], displays a chair conformation with axial phosphoryl oxygen and close to planar geometry at the N atoms. The molecules are linked by N-H⋯O=P hydrogen bonds into chains. One chloroethyl side chain is extended, the other is gauche. The C—Cl bond lengths are Cl1-C5 1.789 (2) and Cl2-C7 1.791 (2) A. The bicyclic degradation product, 1-(2-chloroethyl)tetrahydro-1H,5H–1,3,2-diazaphospholo[2,1-b][1,3,2]Oxazaphosphorine 9-oxide, C7H14ClN2O2P, (2), is formed by intramolecular alkylation at the ring N atom of (1). The major change of bond length upon annelation is observed for P—N2, the ring P—N bond in (1), which is lengthened from 1.633 (2) to 1.6593 (14) A. The angle N1—P—N2, incorporated into the five-membered ring in (2), narrows from 105.84 (8) to 97.36 (7)°. The remaining chloroethyl side chain is gauche. The C—Cl bond length is 1.790 (2) A.
