A new approach to the synthesis of novel bifunctional dinuclear
platinum complexes with linear coordinating
spermidine and spermine is reported. The synthetic pathway
involves first the three-step selective protection of
the polyamines, giving bis(trifluoroacetyl)polyamines
(1, 4),
(tert-butoxycarbonyl)bis(trifluoroacetyl)polyamines
(2, 5), and
(tert-butoxycarbonyl)polyamines (3,
6), respectively. The platination at desired sites with
activated
species of cis- or
trans-[PtCl2(NH3)2]
(CDDP or TDDP, respectively) produces the BOC-protected
dinuclear
species [{cis- or
trans-PtCl(NH3)2}2(μ-L)]X
(7, L = BOC-spermidine, X =
(NO3)0.75Cl1.25; 9,
L = (BOC)2-spermine, X = Cl2; cis spermine species not
isolated). Through final deprotection, three different
complexes
were obtained and further investigated:
[{trans-PtCl(NH3)2}2{μ-spermidine-N
1,N
8}]Cl3
(8),
[{trans-PtCl(NH3)2}2{μ-spermine-N
1,N
12}]Cl4
(10), and
[{cis-PtCl(NH3)2}2{μ-spermine-N
1,N
12}]Cl4
(11). One- and two-dimensional
NMR solution studies provided evidence that 11, at
physiological pH, forms an inert
bis((tetraamine)platinum)
species in which each Pt is chelated by a central and a terminal amino
group. In contrast, complexes 8 and
10
retain their reactivity, showing only reversible formation of hydroxo
bridges. The comparison of in vitro cytotoxicity
data for 8, 10, and 11 with data for
previously described bifunctional dinuclear complexes shows the
enhanced
activity particularly of complex 8 in the CDDP-resistant
L1210 cell line. The binding of 8 and 10 to
poly(dG-dC)·poly(dG-dC) is further increased and also reflected by B
→ Z conformational changes at lower doses.
The ubiquitin-proteasome pathway plays a central role in regulation of the production and destruction of cellular proteins. These pathways mediate proliferation and cell survival, particularly in malignant cells. The successful development of the 20S human proteasome inhibitor bortezomib for the treatment of relapsed and refractory multiple myeloma has established this targeted intervention as an effective therapeutic strategy. Herein, the potent, selective, and orally bioavailable threonine-derived 20S human proteasome inhibitor that has been advanced to preclinical development, [(1R)-1-[[(2 S,3 R)-3-hydroxy-2-[(6-phenylpyridine-2-carbonyl)amino]-1-oxobutyl]amino]-3-methylbutyl]boronic acid 20 (CEP-18770), is disclosed.
Matrix metalloproteinases (MMPs) are a family of zinc endopeptidases that have been implicated in various disease processes. Different classes of MMP inhibitors, including hydroxamic acids, phosphinic acids and thiols, have been previously described. Most of these mimic peptides and most likely bind in a similar way to the corresponding peptide substrates. Here we describe pyrimidine-triones as a completely new class of metalloprotease inhibitors. While the pyrimidine-trione template is used as the zinc-chelating moiety, the substituents have been optimized to yield inhibitors comparable in their inhibition efficiency of matrix metalloproteinases to hydroxamic acid derivatives such as batimastat. However, they are much more specific for a small subgroup of MMPs, namely the gelatinases (MMP-2 and MMP-9).
A series of DNA-intercalating potential antitumor agents, 1-[(omega-aminoalkyl)amino]-4-[N-(omega-aminoalkyl)carbamoyl]-9-oxo-9, 10-dihydroacridines, has been prepared by aminolysis of the corresponding 4-[N-(omega-aminoalkyl)carbamoyl]-1-chloro derivative with a suitable omega-aminoalkylamine. The noncovalent DNA-binding properties of these bis-functionalized compounds have been examined using a combination of fluorometric and thermal denaturation techniques and are compared with the behaviors for established DNA intercalants and cationic minor groove ligands. The results indicate that (i) the agents are considerably more DNA-affinic than less functionalized acridinones, with 'apparent' binding constants of (0.1-2.1) x 10(7) and (0.3-7.5) x 10(7) M-1 at pH 5 and 7, respectively, (ii) overall affinity is sensitive to both the length of the flexible side chain and the complexity of the attached amine substituents, and (iii) the pendant side chains effect a switch to moderate AT-preferential binding. In vitro cytotoxic potencies toward six tumor cell lines broadly parallel the observed DNA affinities, although poor correlation is evident for certain compounds. The octanol/water partition coefficients have been also calculated, but there is no correlation with cytotoxicity values. Two highly DNA-affinic analogs, 10 and 13, have been identified with a useful broad spectrum of cytotoxic activity.
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