Biomedical subjects

D L Boger

Publications and source records attributed to D L Boger.

83 records · Page 5Linked to original sources

PubMed1995

1,2,9,9a-Tetrahydrocyclopropa[c]benz[e]indol-4-one (CBI) analogs of CC-1065 and the duocarmycins: synthesis and evaluation.

An extensive study of analogs of the potent antitumor antibiotics CC-1065 and the duocarmycins which incorporate the 1,2,9,9a-tetrahydrocyclopropa[c]benz[e]indol-4-one (CBI) alkylation subunit are detailed. In contrast to early speculation, deep-seated modifications in the CC-1065 and duocarmycin alkylation subunits are well tolerated and the CBI-based analogs proved to be potent cytotoxic agents and efficacious antitumor compounds. Full details of studies defining a direct relationship between functional stability and in vitro cytotoxic potency are described. As such, the readily accessible CBI-based analogs were found to be four times more stable and four times more potent than the corresponding analogs containing the authentic CPI alkylation subunit of CC-1065 and comparable in potency to agents containing the authentic alkylation subunit of duocarmycin SA. Similarly, the CBI-based agents alkylate DNA with an unaltered sequence selectivity at an enhanced rate and with a greater efficiency than the corresponding CPI analog and were comparable to the corresponding analog incorporating the duocarmycin SA alkylation subunit. Systematic and extensive modifications and simplifications in the DNA binding subunits attached to CBI were explored with the comparisons of both enantiomers of CC-1065 and the duocarmycins 2 and 3 with enantiomers of 18-24, 25-29, 57-61, 62-65, 66-68, 72, 73, 78 and 79.

Alkylation↗

PubMed1995

Key analogs of the tetrapeptide subunit of RA-VII and deoxybouvardin.

The synthesis and evaluation of two key analogs 3 and 4 of the potent antitumor antibiotics deoxybouvardin (1) and RA-VII (2) which contain fundamental modifications in the tetrapeptide subunit are described. Unlike the natural products, these agents 3 and 4, which substitute (Gly)4 and (Gly)3 for the D-Ala-Ala-NMe-Tyr(OMe)-Ala tetrapeptide subunit, adopt conformations in which the central amide in the cycloisodityrosine subunit adopts its inherently preferred trans stereochemistry and both were found to be biologically inactive.

Amino Acid Sequence↗

PubMed1994

Cerebrodiene: a brain lipid isolated from sleep-deprived cats.

We report the isolation of a heretofore unrecognized brain lipid that is present in cerebrospinal fluid of sleep-deprived cats. The molecule appears to be a long-chain base structurally related to sphingosine and sphinganine in which a second unsaturated bond has been introduced. An increase in the degree of unsaturation of a key membrane component is expected to have important physiological consequences.

Animals↗

PubMed1994

Total synthesis and biological properties of novel antineoplastic (chloromethyl)furanoindolines: an asymmetric hydroboration mediated synthesis of the alkylation subunits.

1,2-Dihydro-1-(chloromethyl)-5-hydroxy-8-methyl-3H-furano[3,2-e]in dole (CFI) as a novel replacement of the cyclopropylpyrroloindoline (CPI) alkylation subunit of CC-1065, U-71184, and U-73975 (adozelesin) has been synthesized and incorporated into a series of efficacious antineoplastic agents. A partial solution to an asymmetric synthesis of the CFI alkylation subunit has been achieved by the implementation of an asymmetric hydroboration reaction of an intermediate 3-methyleneindoline (13). Extension to the asymmetric synthesis of the CBI and CI alkylation subunits is presented. The demonstration and comparative study of the sequence-selective DNA alkylation properties of the CFI-based agents are detailed, and the preliminary in vitro and in vivo antineoplastic properties of these agents in the human epidermoid cell lung carcinoma (T222) are described.

Alkylation↗

PubMed1994

Design, synthesis and evaluation of bouvardin, deoxybouvardin and RA-I-XIV pharmacophore analogs.

The synthesis and in vitro cytotoxic evaluation of a key set of cycloisodityrosine subunit analogs of deoxybouvardin and RA-VII are detailed and constitute a complete investigation of the natural product pharmacophore. The studies illustrate that the 18-membered ring tetrapeptide potentiation of the cytotoxic activity of cycloisodityrosine is not likely to be due to simple alteration or constraint of the conformation of the 14-membered cycloisodityrosine subunit and that simple derivatization of cycloisodityrosine may not provide the same potentiation.

Animals↗

PubMed1994

Molecular basis for sequence selective DNA alkylation by (+)- and ent-(-)-CC-1065 and related agents: alkylation site models that accommodate the offset AT-rich adenine N3 alkylation selectivity.

A detailed evaluation of the DNA alkylation selectivity of (+)-CC-1065, ent-(-)-CC-1065 and a series of aborted and extended analogs possessing the CPI alkylation subunit is detailed and the refinement of a model that accommodates the offset AT-rich adenine N3 alkylation selectivity of the enantiomeric agents is presented. The natural enantiomers bind in the minor groove in the 3'-->5' direction starting from the adenine N3 alkylation site across a 2 base (N-BOC-CPI; i.e. 5'-AA), 3.5 base (CPI-CDPI1/CPI-PDE-I1; i.e. 5'-AAA), 5 base (CC-1065/CPI-CDPI2; i.e. 5'-AAAAA) or 6.5 base (CPI-CDPI3; i.e. 5'-AAAAAA) AT-rich site. In contrast, the unnatural enantiomers bind in the reverse 5'-->3' direction in the minor groove and the binding site necessarily starts at the first 5' base preceding the adenine N3 alkylation site and extends across the alkylation site to the adjacent 3' bases covering an AT-rich site of 2 bases (N-BOC-CPI; e.g., 5'-AA), 5 bases (CC-1065/CPI-CDPI2; eg. 5'-AAAAA), or 6.5 bases (CPI-CDPI3; e.g. 5'-AAAAAA). Notably, the model accommodates the unusual observation that both enantiomers of N-BOC-CPI alkylate the same sites within duplex DNA (5'-AA > 5'-TA) and the required reversed binding orientation of the enantiomeric agents. The reversed binding orientation is required to permit access to the electrophilic cyclopropane and the resulting offset AT-rich alkylation selectivity is the natural consequence of the diastereomeric relationship of the adducts. Three dimensional models of the natural and unnatural enantiomer alkylations are presented which clearly illustrate the offset binding sites. A fundamentally simple model for the CC-1065 DNA alkylation reaction, that accommodates the behavior of both enantiomers, is provided in which the sequence selectivity is derived from the noncovalent binding selectivity of the agents preferentially in the narrower, sterically more accessible AT-rich minor groove, the inherent steric accessibility to the adenine N3 alkylation site that accompanies deep penetration of the agent into the minor groove within an AT-rich site, and the 2 base-pair (N-BOC-CPI), 3.5 base-pair (CPI-PDE-I1/CPI-CDPI1), 5 base-pair (CC-1065/CPI-CDPI2), or 6.5 base-pair (CPI-CDPI3) site size required to permit agent binding in the minor groove at the alkylation site.(ABSTRACT TRUNCATED AT 400 WORDS)

Alkylation↗

PubMed1993

Evaluation of functional analogs of CC-1065 and the duocarmycins incorporating the cross-linking 9a-chloromethyl-1,2,9,9a-tetrahydrocyclopropa[c]benz[e]indol-4-on e (C2BI) alkylation subunit.

The DNA alkylation properties and in vitro cytotoxic activity of a series of analogs of CC-1065 and the duocarmycins incorporating the 9a-chloromethyl-1,2,9,9a-tetrahydrocyclopropa[c]benz[e]indol-4-one (C2BI) alkylation subunit are detailed. The C2BI-based agents have been shown to alkylate DNA within the minor groove in a fashion analogous to CC-1065 or duocarmycin. The stereoelectronically-controlled adenine N3 addition to the least substituted cyclopropane carbon occurs with a selectivity that represents a composite of the two enantiomers of the corresponding CBI-based agents. Additional high affinity alkylation sites were detected which were not prominent alkylation sites for either enantiomer of the CBI-based agents. Such sites may represent induced high affinity alkylation sites resulting from DNA cross-linking following complementary strand alkylation at a high affinity alkylation site and each such site detected proved consistent with predicted models of an adenine-adenine cross-linking event. Further, consistent with this interpretation, the C2BI agents were shown to constitute efficient cross-linking agents with DNA cross-linking being observed at the same concentrations as DNA alkylation. In comparison to the parent CBI-based agents, the C2BI-based agents proved to be approximately 100-10,000x less effective at DNA alkylation and 100-10,000x less potent in cytotoxic assays. This is suggested to be the consequence of a significant steric deceleration of the adenine N3 alkylation reaction attributable to the additional 9a-chloromethyl substituent. Consistent with this interpretation, the noncovalent binding constant of C2BI-CDPI2 for poly[dA]-poly[dA]-poly[dT] proved nearly identical to that of CDPI3 under kinetic binding conditions, and prolonged incubation of C2BI-CDPI2 with poly[dA]-poly[dT] (72 h, 25 degrees C) provided covalent complexes with a helix stabilization comparable to that observed with (+)- or (-)-CPI-CDPI2 indicating that the size of the C2BI subunit inhibits but does not preclude productive DNA alkylation.

Alkylation↗

PubMed1991

Demonstration of a pronounced effect of noncovalent binding selectivity on the (+)-CC-1065 DNA alkylation and identification of the pharmacophore of the alkylation subunit.

Studies on the structural origin of the DNA alkylation selectivity of the antitumor antibiotic (+)-CC-1065 are detailed. The sites of alkylation of double-stranded DNA were examined for simple derivatives of 7-methyl-1,2,8,8a-tetrahydrocycloprop[1,2-c]pyrrolo[3,2-e]indol- 4(5H)-one (CPI), (+)-CC-1065, and agents incorporating the parent 1,2,7,7a-tetrahydrocycloprop[1,2-c]indol-4-one (CI) left-hand subunit. The CI subunit of the agents is a much more reactive alkylating agent than the natural CPI alkylation subunit of CC-1065. Consequently, simple derivatives of CI were found to alkylate double-stranded DNA under milder conditions than were simple derivatives of CPI, and the marked similarities in the CI and CPI DNA alkylation profiles illustrate that CI represents the minimum pharmacophore of CPI. Comparisons of the DNA alkylation profiles of (+)-N-butyloxycarbonyl-CPI, (+)-N-acetyl-CPI, and (+)-CC-1065 revealed distinctions in the CPI and (+)-CC-1065 sites of alkylation, whereas the incorporation of the reactive CI electrophile into an analog of CC-1065 (CI-CDPI2) (CDPI, N3-carbamoyl-1,2-dihydro-3H-pyrrolo[3,2-e]indole-7-carboxylic acid) provided an agent that possesses the characteristic CC-1065 DNA alkylation profile (site selectivity and relative site intensity). These observations suggest that the noncovalent binding selectivity of the agents may restrict the number of available DNA alkylation sites and play a productive role in controlling the sequence-selective alkylation by effectively delivering the electrophile to A + T-rich minor groove regions of DNA possessing accessible adenine N-3 alkylation sites. In turn, the noncovalent binding selectivity may be derived from preferential binding within the narrower, sterically more accessible A + T-rich minor groove of double-stranded DNA.

Alkylation↗

PubMed1990

A demonstration of the intrinsic importance of stabilizing hydrophobic binding and non-covalent van der Waals contacts dominant in the non-covalent CC-1065/B-DNA binding.

The comparative DNA binding properties and cytotoxic activity of CDPIn methyl esters (n = 1-5) vs. PDE-In methyl esters (n = 1-3) are detailed in studies which provide experimental evidence for the intrinsic importance of stabilizing hydrophobic binding and non-covalent van der Waals contacts dominant in the CC-1065/B-DNA minor groove binding. High affinity minor groove binding to DNA was established through: (1) the observation of CDPI3 binding (UV) but not unwinding of supercoiled DNA (phi 174 RFI DNA) thus excluding intercalative binding; (2) the observation of CDPI3 binding to T4 phage DNA (UV, delta Tm) in which the major groove is occluded by glycosylation thus excluding major groove binding; (3) the observation of salt (Na+) concentration independent high affinity CDPI3 binding to poly(dA . poly(dT) thus excluding simple electrostatic binding to the DNA phosphate backbone; and further inferred through (4) the observation of an intense induced dichroism (ICD, poly(dA) . poly(dT) and poly(dG) . poly(dC) [phi]23(358) = 24,000 and 23,500). This high affinity minor groove binding is sufficient to produce a potent cytotoxic effect.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMed1987

Streptonigrin and lavendamycin partial structures. Probes for the minimum, potent pharmacophore of streptonigrin, lavendamycin, and synthetic quinoline-5,8-diones.

The preparation and evaluation of 7-amino-5,8-dioxo-2-(2'-pyridyl)quinoline-6'-carboxylic acid (5a) and 7-amino-2-(2'-aminophenyl)-5,8-dioxoquinoline-5'-carboxylic acid (6a) constituting potential minimum, potent pharmacophores of streptonigrin (1a) and lavendamycin (2a), two structurally related naturally occurring antitumor antibiotics, are detailed. In contrast to observations associated with streptonigrin and lavendamycin in which the C-ring C-6' carboxylic acid potentiates the antitumor, antimicrobial, and cytotoxic properties of the naturally occurring, substituted 7-aminoquinoline-5,8-dione AB ring systems, the C-6'/C-5' carboxylic acid of 5a/6a diminishes the observed antimicrobial and cytotoxic properties of the 2-(2'-pyridyl)- and 2-(2'-aminophenyl)-7-aminoquinoline-5,8-diones. A direct comparison of the antimicrobial and cytotoxic properties of a complete set of streptonigrin and lavendamycin partial structures is detailed in efforts to define the role peripheral substituents play in potentiating the biological properties of the naturally occurring and synthetic agents bearing the 7-aminoquinoline-5,8-dione AB ring system and in efforts to define the minimum, potent pharmacophore of the naturally occurring antitumor antibiotics. The relationship of these observations to a chemical mechanism of cellular toxicity is discussed.

Animals↗

PubMed1985

Antimicrobial and cytotoxic properties of 9,10-dihydrophenanthrenes: structure-activity studies on juncusol.

The antimicrobial and cytotoxic properties of a series of 9,10-dihydrophenanthrenes structurally related to juncusol (1a), a postulated phytoalexin with confirmed cytotoxic properties, are detailed. Two simple 9,10-dihydrophenanthrenes, 2,7-dihydroxy-3,8-dimethyl-9,10-dihydrophenanthrene (2h, desvinyljuncusol) and 2-hydroxy-3-methyl-9,10-dihydrophenanthrene (3h), were found to possess in vitro antimicrobial activity comparable with that of the natural product. Two 9,10-dihydrophenanthrenes substituted with quaternary ammonium salts, 2d and 3d, each containing a reactive benzylic dimethyl[(phenylthio)methyl]ammonio group, were found to be 10-20 times more potent than juncusol (1a). Confirmed in vitro cytotoxic activity that parallels antimicrobial activity was found for juncusol (1a), desvinyljuncusol (2h), 2-hydroxy-3-methyl-9,10-dihydrophenanthrene (3h), and the quaternary dimethyl[(phenylthio)methyl]ammonium salts 2d and 3d in a human lymphoblastic leukemia cell culture (CCRF-CEM, IC50 = nt, 9.3, nt, 0.9 and 1.4 microgram/mL, respectively), B-16 mouse melanoma cell culture (IC50 = 12.5, 17.5, 27.7, 0.3, and 0.5 microgram/mL, respectively), and L-1210 mouse lymphocytic leukemia cell culture (IC50 = 13.8, 10.2, 24.5, 1.3, and 3.7 micrograms/mL, respectively). The comparable potency and spectrum of activity of juncusol (1a), desvinyljuncusol (2h), and 2-hydroxy-3-methyl-9,10-dihydrophenanthrene (3h) suggest that the agents are acting as simple phenols in exerting their antimicrobial and cytotoxic effects.

Animals↗