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J W Lown

Publications and source records attributed to J W Lown.

At least 19 recordsLinked to original sources
PubMed2002

DNA sequence recognition of thiazole-containing cross-linked polyamides can be favored.

The binding ability of cross-linked thiazolated polyamides (containing the base sequence-reading elements thiazole(Th)-pyrrole(Py)-pyr-role(Py) and thiazole(Th)-imidazole(Im)-pyrrol(Py) to various DNA dodecamers has been investigated. CD titration experiments at high salt concentration demonstrate that the dimers with a heptanediyl linker (C7 dimer) show a significantly higher sequence specificity than their corresponding monomers. The dimer of Th-Py-Py primarily prefers binding to pure AT sequences and that of Th-Im-Py to the dodecamer sequences containing a GC pair within the central sequence (e.g. AACGTT). Surprisingly, the sequence binding ability is strongly influenced by the presence of a T-A step: e.g. Th-Py-Py has a similar affinity to the sequences TTTAAA and ATCGTA; likewise Th-Im-Py shows a preference for these sequences. The CD results correlate with footprinting data. Related biochemical studies on the effect of polyamides on DNA gyrase activity in vitro show that the C7 dimers most effectively inhibit the enzyme activity compared with the monomers and the natural reference minor groove binder distamycin. The highest inhibitory potency is observed for the Th-Py-Py-dimer. The role of the T-A step in binding of the cross-linked dimer to the minor groove is discussed in light of the sequence recognition of the TATA box binding protein.

AT Rich Sequence↗
PubMed2001

Design, synthesis, and intracellular localization of a fluorescently labeled DNA binding polyamide related to the antibiotic distamycin.

The design and synthesis of the lipophilic (9) and fluorescent (10) conjugates of a structural analogue of distamycin and their in vitro cellular localization studies are reported. Confocal laser scanning microscopy (CLSM) indicates that 10 rapidly enters human ovarian adenocarcinoma (SKOV-3) cells with principal uptake in mitochondria and uniform cytoplasmic distribution.

Antiviral Agents↗
PubMed2001

RNase activity of a DNA minor groove binder with a minimalist catalytic motif from RNase A.

Imidazole and compounds containing imidazole residues have been shown to cleave RNA in an RNase A-mimicking manner. Di-imidazole lexitropsin is a compound which is derived from the polyamide drugs distamycin and netropsin essentially by the replacement of two pyrrole heterocycles with N-methyl-imidazole residues. This enables it to bind to the minor groove of B-DNA in a sequence-specific manner. We demonstrate here that this lexitropsin derivative has RNA cleavage activity, as tested on model RNAs. Optimal cleavage conditions and cleavage specificity resemble those known from other imidazole conjugates and are thus consistent with an RNase A type cleavage mechanism. The optimum concentration of the compound for cleavage is similar to previously investigated imidazole-based RNase mimics. As a whole new class of chemical compounds capable of interacting with nucleic acids through extensive hydrogen bonding, these imidazole containing compounds constitute promising scaffolds and ligands, for the construction of novel RNase mimics with high affinity.

Animals↗
PubMed2001

Recent developments in sequence selective minor groove DNA effectors.

DNA is a well characterized intracellular target but its large size and sequential nature make it an elusive target for selective drug action. Binding of low molecular weight ligands to DNA causes a wide variety of potential biological responses. In this respect the main consideration is given to recent developments in DNA sequence selective binding agents bearing conjugated effectors because of their potential application in diagnosis and treatment of cancers as well as in molecular biology. Recent progress in the development of cross linked lexitropsin oligopeptides and hairpins, which bind selectively to the minor groove of duplex DNA, is discussed. Bis-distamycins and related lexitropsins show inhibitory activity against HIV-1 and HIV-2 integrases at low nanomolar concentrations. Benzoyl nitrogen mustard analogs of lexitropsins are active against a variety of tumor models. Certain of the bis-benzimidazoles show altered DNA sequence preference and bind to DNA at 5'CG and TG sequences rather than at the preferred AT sites of the parent drug. A comparison of bifunctional bizelesin with monoalkylating adozelesin shows that it appears to have an increased sequence selectivity such that monoalkylating compounds react at more than one site but bizelesin reacts only at sites where there are two suitably positioned alkylation sites. Adozelesin, bizelesin and carzelesin are far more potent as cytotoxic agents than cisplatin or doxorubicin. A new class of 1,2,9,9a-tetrahydrocyclo-propa[c]benz[e]indole-4-one (CBI) analogs i.e., CBI-lexitropsin conjugates arising from the latter leads are also discussed.A number of cyclopropylpyrroloindole (CPI) and CBI-lexitropsin conjugates related to CC-1065 alkylate at the N3 position of adenine in the minor groove of DNA in a sequence specific manner, and also show cytotoxicities in the femtomolar range. The cross linking efficiency of PBD dimers is much greater than that of other cross linkers including cisplatin, and melphalan. A new class of PBD-lexitropsin conjugates is also discussed. Certain functional models of the bleomycins (BLMs) show outstanding DNA cleavage activity comparable with that of and positionally distinct from natural BLM.

Animals↗
PubMed2001

Novel cyclopropylindole conjugates and dimers: synthesis and anti-cancer evaluation.

There is a considerable interest currently in the development of DNA sequence specific or selective agents for genetic targeting for the control of gene expression, for application in diagnosis or ultimately in therapy. In this context CC-1065 is one of the most impressive lead compounds isolated in trace quantities from the culture of Streptomyces zelensis at Upjohn in 1978. The unique structure was confirmed by single X-ray in 1981. However CC-1065 cannot be used in humans because it was found that it caused delayed deaths in experimental animals. In the search for compounds with better antitumor selectivity and DNA sequence specificity many CC-1065 analogs have been synthesized in an attempt to avoid the undesired side effects while retaining its potency against tumor cells. Two successful attempts in the modification in the active moiety of the parent natural product 1,2,8,8a-tetrahydro-7-methylcyclopropa[3,2-e]indole-4-one (CPI) and 1,2,9,9a-tetrahydrocyclopropa[c]benz[e]indole-4-one (CBI) have been made. We review here recent progress with the analogs of CPI and CBI and their conjugates both by solution and solid phase, also the progress and development of CPI and CBI conjugates with polyamides (information reading molecules in the minor groove of DNA). Since CPI-CPI dimers are significantly more potent than CC-1065 in vitro and in vivo, a large number of CBI-CBI dimers with varying linkers lengths and positions synthesized in our group and their pharmacological properties have been reviewed.

Animals↗
PubMed2001

Ab initio studies of the reaction of hydrogen transfer from DNA to the calicheamicinone diradical.

BACKGROUND: The biological activity of enediyne chemotherapeutic (anti-cancer) agents is attributed to their ability to cleave duplex DNA. Part of the reaction of cleavage is the abstraction of hydrogens from the deoxyribose moiety of DNA by the biradical formed via a Bergman rearrangement. METHODS: The mechanism of the reaction of abstraction of two hydrogen atoms from two deoxyribophosphate molecules by the calicheamicinone biradical is studied with ab initio calculations at Hartree-Fock and post-Hartree-Fock level. The Titan program is used to perform the calculations. RESULTS: It is found that the reactions are exothermic and thus thermodynamically reasonable. CONCLUSIONS: The mechanism of DNA cleavage by the enediyne-containing drugs is likely to proceed by the abstraction of the hydrogens from deoxyribose by the biradical formed by the drug. Further studies should determine in which way the modification of the drug's structure would make this reaction even more exothermic and, thus, more likely to occur.

Aminoglycosides↗
PubMed2000

Design and synthesis of novel thiazole-containing cross-linked polyamides related to the antiviral antibiotic distamycin.

A family of naturally occurring oligopeptides includes netropsin, distamycin, anthelvencin, kikumycin B, amidinomycin, and norformycin. Netropsin (I) and distamycin (II) express their biological activities by targeting specific sequences of chemical functionalities in the minor groove of DNA. Both netropsin and distamycin can be regarded as polyamide chains in which each alpha-carbon has been replaced by a five-membered pyrrole ring. The repeat distance in such an augmented polyamide chain is almost the same as the distance from one base pair to the next along the floor of a minor groove within beta-DNA. In this paper we report the synthesis of 16-21 cross-linked polyamides containing a thiazole heterocyclic ring bearing the active functionalites NH(2), NHCHO, or H. 16 and 17 were synthesized by DCC and HOBt catalyzed reaction of 5 with 14 and 15, while the formylation products 18 and 19 were obtained by coupling the formylated 4-methyl-thiazolated acid 6 with 14 and 15. The deaminated compounds 20 and 21 were obtained by the coupling of 5-trichloroacetyl-4-methylthiazole 7 synthesized from 4-methylthiazole. All the six cross-linked polyamides 16-21 were tested for their DNA gyrase inhibition. The studies have shown these polyamides have better sequence recognition and a greater percentage of inhibition than the corresponding monomers. The compound 17 shows complete inhibition of gyrase at 0.5 microM concentration as compared to the naturally occurring distamycin at 1.0 microM.

Antiviral Agents↗
PubMed2000

Design, synthesis and cytotoxicity evaluation of 1-chloromethyl-5-hydroxy-1,2-dihydro-3H-benz[e]indole (seco-CBI) dimers.

Three types of 1-chloromethyl-5-hydroxy-1,2-dihydro-3H-benz[e]indole (seco-CBI) dimers were designed, synthesized and evaluated in vitro by NCI against nine types of cancer cells. Biological results showed that the antitumor activities of these seco-CBI dimers were strongly related to the position and length of the linker and generally with potency increasing in the order of C7-C7 dimers (22i-iv) < C7-N3 dimers (28i-iv) < N3-N3 dimers (25i-iv). Compound 28iv showed significant activity against CCRT-CEM, HL-60 (TB), MOLT-4, and SR leukemia cell lines and the MCF 7 breast cancer cell line with GI50 values < 0.01 microM. N3-N3 dimer 25i displayed striking potency against leukemia, CNS cancer, melanoma and prostate cancer cell lines with GI50 values < 0.01 microM against all the cell lines and showed the highest overall potency of the agents examined (GMG=0.0120 microM).

Antineoplastic Agents, Alkylating↗
PubMed2000

Ab initio calculations on (-)-calicheamicinone and some of its reactions involved in its activation and interaction with DNA.

Ab initio calculations were performed on (-)-calicheamicinone, and on the product (Z or E) of the Michael addition via a reaction with methanethiol. It is found that the sulfur moiety position versus the rest of the molecule is quite flexible. The Michael adduct featuring the carbamate group E to the sulfur moiety is more stable than the Z isomer. The Bergman reaction of the diradical formation is strongly exothermic.

Aminoglycosides↗
PubMed2000

Semi-empirical, ab initio and molecular modeling studies on the DNA binding of a calicheamicinone-polyamide conjugate.

AM1 semi-empirical and ab initio calculations were performed on certain synthetic polyamide conjugates of the aglycone of the minor groove binding antibiotic calicheamicin. Geometry optimized conformations and heats of formation were obtained. The binding of the optimized conformations of the drug to both alternating and non-alternating (AT)n and to (G)n x (C)n sequences were studied and the energies of binding were compared to each other. The results can be utilized in the design of novel enediyne-based drugs.

Aminoglycosides↗
PubMed2000

Shape-selective binding of geometrically-constrained bis-distamycins to a DNA duplex and a model Okazaki fragment of identical sequence.

The binding of ligands to nucleic acids is of great interest for the control of gene expression and other nucleic acid mediated processes. We have evaluated the binding of several geometrically-constrained bis-distamycins to a model Okazaki fragment [OKA], or a DNA duplex having identical base sequence [DD], using gel-shift assays, optical spectroscopy and differential scanning calorimetry. In the case of covalent attachment of two distamycins to a central benzene ring, a similar binding profile was observed for [DD] as was observed for [OKA] (para binds [K(app) > 10(6) M(-1)], meta binds only weakly). For a central pyridyl ring, however, clear distinction between the binding to [DD] and binding to [OKA] was observed. While none of the three meta isomers having a central pyridyl ring bound [OKA], two of them (MT-17 and MT-12) bound [DD] [K(app) > 10(6) M(-1)]. These results demonstrate subtle differences in lexitropsin shape and placement of electronegative atoms may result in selective binding to a nucleic acid duplex based both on base sequence and chemical composition. Selective binding to DNA duplexes may be useful for designing ligands that regulate transcription, but do not interfere in other nucleic acid mediated processes.

Base Sequence↗
PubMed2000

Synthesis and antitumor cytotoxicity evaluation of pyrido[4,3,2-de]quinolines and isoquinolino[6,5,4,3-cde]quinolines.

A series of novel pyrido[4,3,2-de]quinoline and isoquinolino[6,5,4,3-cde] quinoline compounds was synthesized and evaluated for cytotoxicity in the National Cancer Institute developmental therapeutics program. The tricyclic compound 7 was synthesized by the cyclization of 3,4-diamino-1,2dimethoxybenzene with diethyl 1,3-acetonedicarboxylate. Oxidation of monochloropyrido[4,3,2-de]quinoline 8 selectively produced 2,3-diketopyrido[4,3,2-de]quinoline 9 as deep violet crystals. Compound 9, when treated with acetone or acetophenone, affords the tetracyclic isoquinolino[6,5,4,3-cde]quinolines 13 and 14, respectively. 2,3-Diketopyrido[4,3,2-de]quinolines 9 and 10 exhibit higher cytotoxic potency than isoquinolino[6,5,4,3-cdelquinolines 13, 14, 15 and 16. Compound 9 selectively affects the cell growth against leukemia CCRF-CEM and HL-60 cell lines, the non-small cell lung cancer HOP-92 cell line, and breast cancer MDA-MB231/ ATCC and MDA-MB- 435 cell lines with GI(50) values of <2.0 microM. Modification of compound 9 with an ester group at the N-1 position afforded compound 10, which exhibits a wide spectrum of anticancer activities with a mean graph midpoint value of 1.8 microM against the 60 cancer cell lines.

Antineoplastic Agents↗
PubMed2000

Design, synthesis and in vitro cytotoxicity studies of novel pyrrolo[2,1-c][1,4]benzodiazepine (PBD)--polymade conjugates and 2,2'-PBD dimers.

A series of novel pyrrolo[2,1-c][l,4]benzodiazepine (PBD)-polyamide conjugates (1 and 2) and 2,2'-PBD dimers (3, 4 and 5) were synthesized and evaluated for cytotoxicity in >60 human tumor cell lines. In general PBD-polyamide conjugates (1 and 2) exhibit higher cytotoxic potency compared with 2,2'-PBD dimers (3, 4 and 5). Compound 2 exhibits a wide spectrum of anticancer activities against 17 cell lines in six cancer panels with LC50 values of <9 microM, and is especially effective against colon cancer, melanoma, renal cancer and breast cancer. Compound 1 selectively affects cell growth against renal cancer A 498 cell line and compound 4 affects cell growth against breast cancer MDA-MB-231/ATCC cell line with an LC50 value 0.06 microM. Increases in the chain length of the linker in 2,2'-PBD dimers significantly increase the cytotoxic potency and increases in the number of pyrrole groups in the PBD-polyamide conjugates similarly increase the cytotoxic potency.

Antineoplastic Agents, Alkylating↗
PubMed2000

Design, synthesis and antitumor cytotoxicity of novel bis-benzimidazoles.

A series of novel bis-benzimidazoles, IIa-e, IIIa-e and IVa-g, was designed, synthesized and evaluated for anticancer properties. Certain additional analogs were also designed by introducing the p-quinone moiety, a characteristic feature found in mitomycin C, indolequinones and other examples of bioreductively activated alkylating agents. Structural changes of the bis-benzimidazole nucleus with various leaving groups were investigated for their effects on their pharmacological properties. These compounds were evaluated for their cytotoxicity against human cancer cell lines. The results of the studies indicate that the compounds IIa, IIc, IVa, IVc, IVd and IVg possess significant cytotoxic activities against 22 cell lines in seven cancer panels with GI50 values between <0.01 and 99.5 microM especially in the cases of renal cancer, CNS cancer, colon cancer, melanoma and breast cancer.

Antineoplastic Agents, Alkylating↗
PubMed1999

Synthetic DNA minor groove-binding drugs.

In this review, both cationic and neutral synthetic ligands that bind in the minor groove of DNA are discussed. Certain bis-distamycins and related lexitropsins show activities against human immunodeficiency virus (HIV)-1 and HIV-2 at low nanomolar concentrations. DAPI binds strongly to AT-containing polymers and is located in the minor groove of DNA. DAPI intercalates in DNA sequences that do not contain at least three consecutive AT bp. Berenil can also exhibit intercalative, as well as minor groove binding, properties depending on sequence. Furan-containing analogues of berenil play an important role in their activities against Pneumocystis carinii and Cryptosporidium parvuam infections in vivo. Pt(II)-berenil conjugates show a good activity profile against HL60 and U-937 human leukemic cells. Pt-pentamidine shows higher antiproliferative activity against small cell lung, non-small cell lung, and melanoma cancer cell lines compared with many other tumor cell lines. trans-Butenamidine shows good anti-P. carinii activity in rats. Pentamidine is used against P. carinii pneumonia in individuals infected with HIV who are at high risk from this infection. A comparison of the cytotoxic potencies of adozelesin, bizelesin, carzelesin, cisplatin, and doxorubicin indicates that adozelesin is a potent analog of CC-1065. Naturally occurring pyrrolo[2,1-c][l,4]benzodiazepines such as anthramycin have a 2- to 3-bp sequence specificity, but a synthetic PBD dimer spans 6 bp, actively recognizing a central 5'-GATC sequence. The crosslinking efficiency of PBD dimers is much greater than that of other major groove crosslinkers, such as cisplatin, melphalan, etc. Neothramycin is used clinically for the treatment of superficial carcinoma of the bladder.

Animals↗
PubMed1999

Rational recognition of nucleic acid sequences.

Recent progress in synthetic and computational chemistry has made it possible to develop certain novel drug candidates. Drug candidates for genetic diseases, such as cancer, may also be designed on the basis of structural information obtained using X-ray analysis and NMR, as well as evidence from biological techniques applied to natural products - DNA (or RNA) complexes and conjugates. The resulting designed drug candidates exhibit promising performance based on the recognition on nucleic acid sequences.

Alkylating Agents↗
PubMed1999

Shape-selective recognition of a model Okazaki fragment by geometrically-constrained bis-distamycins.

Okazaki fragments represent interesting targets for the design of anticancer drugs because of their selective occurrence during DNA replication, a process often elevated in aggressive malignancies. Structural studies have indicated a bend occurs in the helical axis at the junction region (JR) that joins the DNA duplex region (DDR) and the RNA-DNA hybrid duplex region (HDR) of model Okazaki fragments. To identify a structural motif that provides a shape complementary to the Okazaki fragment minor groove, we have investigated the binding of geometrically-constrained bis-distamycins to a model Okazaki fragment, [OKA], with a sequence derived from the genome of simian virus 40 (SV40). Both the JR and the DDR of [OKA] contain consecutive A/T base pairs that could accommodate distamycin binding. Of the six bis-distamycins selected for analysis, the two with a para configuration of the distamycins on the benzene or pyridine scaffold bound [OKA] tightly (Kd approximately 10(-6) M from gel-shift assays; Kd approximately 10(-8) M from deltaT(M)) while the four with a meta orientation did not bind. The two mono-distamycins studied also did not bind [OKA]. Molecular modeling of the complex between the para bis-distamycin MT-9 and [OKA] revealed MT-9 adopted an S- shape complementary to the minor groove of the model Okazaki fragment.

Antineoplastic Agents↗