The kinetics of DNA damage by bleomycin (BLM) was assessed by measuring the amount of DNA breakage induced by BLM at different doses, treatment lengths, and treatment temperatures. DNA degradation was measured with the alkaline unwinding method. Comparison of the curves of DNA cleavage by BLM leads to the conclusion that low doses (1–5 μg/ml) and short treatments (5–15 min) produce marked damage in the DNA. High increases in BLM concentration produce relatively small increases in DNA damage above the levels obtained with low doses. Extension of treatment times does not increase the DNA degradation above the rate observed with 15-min treatments. The repair of DNA damage starts at about 15 min after the initiation of treatment. The mending of DNA breaks is very fast and extensive when BLM is no longer present. Repair not only implies the closing of DNA nicks, but very likely the degradation of the BLM molecules intercalated in the DNA interrupting the reactions responsible for the generation of free radicals. Persistence of BLM in the cell environment facilitates the replacement of degraded BLM molecules by new ones. This produces the persistent production of free radicals and the establishment of a balance between the processes of DNA damage and repair.

The kinetics of DNA damage by bleomycin in mammalian cells.

The bleomycin-mediated degradation of DNA is stimulated (amplified) by certain DNA binding compounds, such as polyamines, that distort the double helix. Computer modelling studies suggest that putrescine (1), spermidine (2), and spermine (3) bind preferentially on the floor of the major groove of (dGdC)5.(dGdC)5. This interaction results in a bend of the oligomer helix toward the major groove and enlargement of the minor groove, both effects being in the order 1 less than 2 less than 3. These polyamine-induced distortions, as obtained from theoretical studies, parallel the experimental values of the amplification activities of 1-3 in the bleomycin-mediated degradation of poly(dGdC).poly(dGdC). The amplification mechanism of non-competitive binding of amplifier molecules in the major groove, and bleomycin in the minor groove, is proposed. It is suggested that the amplifier-induced conformational changes of the DNA helix increase affinity of the activated bleomycin complex toward the DNA minor groove and, consequently, result in an increased efficiency of the bleomycin-mediated degradation of the helix.

Molecular basis for potentiation of bleomycin-mediated degradation of DNA by polyamines. Experimental and molecular mechanical studies.

In the field of natural peptides, beta-lactams, and related compounds, recent exciting developments are discussed. The increasing interest in this class of bioactive amino-acid derived structures has been attributed to the use of new directed screens (enzyme inhibition assays, beta-lactam detection, immunomodulator studies), new and improved applications (antibiotic, transplantation, and cancer chemotherapy), and advances in functional studies (DNA binding peptides, nucleotide complexones, cell wall and protein processing inhibitors). Peptides offer unique access to modifications and analog production by in vivo (directed biosynthesis) and in vitro procedures (enzymatic synthesis) due to their general linear precursors permitting point replacements. Of special interest are recent developments in the genetics of these compounds (cyclic peptides and beta-lactams), which will find applications in production methods in the near future.

Peptide antibiotics, beta-lactams, and related compounds.

(e, 2e) [AM83b, TMC84]. (n−) [MOT83]. (N − 1) [Mor89]. + [AM82, BNK86, Bow86, ES81, GT86, GT87a, GM86a, KU80, KS89b, KM89b, LB83, RBL84, SBE87, SS84b, SS87, YKZ89]. 1/Z [PS84]. $104.75 [Pic83b]. 12 [KU80]. 14 [SST84]. $15.00 [Mår80]. 1s [NMK84, Ten88b]. 1s2pJp ′ jJ [ST84]. 1s2s [DS80a]. 1s2s2pjJ [ST84]. 1s2s 2 [ST84]. 1s2s [DS81c]. 2 [BW85, MOT83, MK83, ddF86]. $26.25 [Wol81]. $28.50 [Pic83a]. 2′ [LMG85, SP82a]. 2: 1 [GP83a]. 3 [BW85, ddF86]. 3′ [KG80]. 3d [WS80b]. $49.00 [Sie83a]. 4L [FEKC84]. 4L+ 2 [FEKC84]. 4× 4 [Lin81a]. $59.00 [Gos80]. 5d [CPGP83]. $85.00 [LM81]. $88.00 [Mår82]. $9.95 [Lun82]. < pu|∂/∂v|s > [JL85]. < r−1 12 > [BB81a]. < r−1 1 > [BB81a]. = [Dat82, KU80, PXLC86, PFLB83, WBK86]. + [CEB86, CLM80, CD89a, CC82b, Con87, DF89, DLVÖ84, EY82, ESKG83, GLLOB88, GP82, JŻ85, Kog84, Kun86, LPS83b, NMK84, PC83b, Sch80a,

A Bibliography of Publications in The International Journal of Quantum Chemistry: 1980{1989

One of the central problems in the study of the mechanism of DNA-antitumor drug interactions is the existence and nature of sequence specificity with respect to the base pairs of DNA. Results of a theoretical exploration of this problem are presented for a particularly important group of such drugs, namely the groove binding ligands. The great majority of the investigated antitumor agents of this category show a marked specificity for the minor groove of AT sequences of B-DNA. Contrary to current concepts and some proposals, hydrogen bond formation between the ligands and the receptor bases of DNA or contacts between specific hydrogen atoms on the ligand and on the bases do not appear to be the main determinants of this specificity. The essential factor responsible for this preference is the strong concentration of the electrostatic molecular potential in this groove of these sequences in B-DNA. This distribution of the potential renders difficult the conception of drugs specific for the minor groove of GC sequences and is responsible for the failure in this respect of lexitropsins and isolexins. Nevertheless, for the first time in theoretical computations, a particular isolexin was conceived which should bind preferentially to the minor groove of GC sequence: this is a neutral ligand composed of three furan or imidazole rings linked by NH groups. An increased GC specificity is, moreover, predicted for vinylexins (analogs of isolexins with C=C linkers) and an increased binding energy, with the specificity conserved, may be obtained for monocationic such ligands. In fact, monocationic vinylexins should form a family of universal groove binding ligands, the AT or GC specificity of which may be dictated by the arrangement of their hydrogen bond donor or acceptor heteratomic ring systems.

Molecular Mechanisms of Specificity in DNA-Antitumor Drug Interactions

The efficacy of COVID‐19 convalescent plasma (CCP) as a treatment for hospitalized patients with COVID‐19 remains somewhat controversial; however, many studies have not evaluated CCP documented to have high neutralizing antibody titer by a highly accurate assay. To evaluate the correlation of the administration of CCP with titer determined by a live viral neutralization assay with 7‐ and 28‐day death rates during hospitalization, a total of 23 118 patients receiving a single unit of CCP were stratified into two groups: those receiving high titer CCP (>250 50% inhibitory dilution, ID50; n = 13 636) or low titer CCP (≤250 ID50; n = 9482). Multivariable Cox regression was performed to assess risk factors. Non‐intubated patients who were transfused with high titer CCP showed 1.1% and 1.7% absolute reductions in overall 7‐ and 28‐day death rates, respectively, compared to those non‐intubated patients receiving low titer CCP. No benefit of CCP was observed in intubated patients. The relative benefit of high titer CCP was confirmed in multivariable Cox regression. Administration of CCP with high titer antibody content determined by live viral neutralization assay to non‐intubated patients is associated with modest clinical efficacy. Although shown to be only of modest clinical benefit, CCP may play a role in the future should viral variants develop that are not neutralized by other available therapeutics.

https://onlinelibrary.wiley.com/doi/pdfdirect/10.1002/ajh.26531

Early administration of COVID‐19 convalescent plasma with high titer antibody content by live viral neutralization assay is associated with modest clinical efficacy

An intercalation model of a complex between DNA and a bleomycin fragment (BLMF), consisting of the bithiazole core and an amide and a protonated amino substituent, is presented. The model, which shows a preference for BLMF with the protonated amine in the minor groove and the acetyl terminal inserted into either the minor and major grooves, respectively, agrees with recently obtained nmr data. The selection of sites I and II, which have the smallest unwinding of the three theoretical intercalation sites, is consistent with the experimental unwinding angle of 12°. The bithiazole moiety stacks between two base pairs of the double helix, while the protonated substituent interacts ionically with the negatively charged regions of the backbone in the minor groove of the DNA. The protonated amine also forms an intramolecular hydrogen bond with the carbonyl oxygen of the amide group on the same substituent. Analysis of drug complexes with different base-pair sequences reveal four energetically defined groups. The relative energy of the dimer duplex complexes of BLMF correlates with bleomycin's observed base-sequence specificity upon cleavage. The most stable intercalation complexes form adjacent to the bases cleaved most readily. This correlation suggests a primary connection between intercalation and cleavage. A model cleavage site based on these preliminary theoretical calculations and the experimental observations is proposed. It consists of an intercalation site in a trimer duplex. Pyrimidine(p)purine sequences are the predominant sites for intercalation, and the base adjacent to the site at the (3′) end is cleaved.

Interactions of molecules with nucleic acids. XII. Theoretical model for the interaction of a fragment of bleomycin with DNA

Binding positions, conformations, and relative minimum binding energies of thioxanthenones, lucanthone, and N-methyllucanthone are calculated for intercalation complexes with DNA in the theoretically determined principal intercalation sites I and II. The optimum binding position of thioxanthenone is identical to that for the chromophore in lucanthone and in its N-methyl derivative. Intercalative binding is optimized in lucanthone and N-methyllucanthone because the chromophore is not disrupted by substituents, and the amino side chain conforms to the phosphate backbone without an increase in conformational energy over that of the free molecule. N-methyl substitution of lucanthone results in a reorientation of the NCH2-CH2NH(+)(CH2CH3)2 substituent and a net loss in electrostatic energy resulting in a decrease of 17.9 kcal in the total binding energy. This result is consonant with the experimental observation that N-methyllucanthone does not intercalate into DNA, whereas lucanthone does. Specificity for base pair sequences in intercalation complexes with lucanthone is attributed primarily to the energy required to open B-DNA to an intercalation site and secondarily to the orientation of the terminal protonated nitrogen toward the carbonyl oxygen on cytosine. Both of these effects enhance the preference for one base. Because the distribution of base pairs G-C and A-T in all 16 dimer duplex intercalation complexes is uniform throughout the range of energy of the complexes, base pair specificity should not be observed for a random distribution of G-C and A-T. However, there is a sequence specificity for synthetic DNA in the order of decreased binding: poly(dC)-poly(dG) > poly(dA-dT)-poly(dA-dT) > poly(dG-dC)-poly(dG-dC) > poly(dA)-poly(dT).

Interactions of molecules with nucleic acids. V. Intercalation of thioxanthenones into DNA

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Early administration of COVID‐19 convalescent plasma with high titer antibody content by live viral neutralization assay is associated with modest clinical efficacy

Interactions of molecules with nucleic acids. XII. Theoretical model for the interaction of a fragment of bleomycin with DNA

Interactions of molecules with nucleic acids. V. Intercalation of thioxanthenones into DNA