Development of functional poly(amido amine) CXCR4 antagonists with the ability to mobilize leukocytes and deliver nucleic acids.

CXCR4 chemokine receptor plays a crucial role in metastatic spread of multiple types of cancer. The present study reports on synthesis of functional polymers based on newly synthesized CXCR4-inhibiting monomers. The resultant linear polymeric CXCR4 antagonists (PCX) show improved ability to inhibit CXCR4 when compared with the monomers.

Cyclam-based polymeric copper chelators for gene delivery and potential PET imaging.

A series of reducible polycationic copper chelators (RPCs) based on 1,4,8,11-tetraazacyclotetradecane (cyclam) were synthesized by Michael addition. Molecular weight of the polycations was controlled by reaction stoichiometry and reaction conditions, resulting in polymers with molecular weights ranging from 4400 to 13 800. The cyclam moieties in the polycations retained their ability to form complexes with Cu(II).

Dual-function CXCR4 antagonist polyplexes to deliver gene therapy and inhibit cancer cell invasion.

A bicyclam-based biodegradable polycation with CXCR4 antagonistic activity was developed with potential for combined drug/gene cancer therapies. The dual-function polycation prevents cancer cell invasion by inhibiting CXCL12 stimulated CXCR4 activation, while at the same time efficiently and safely delivers plasmid DNA into cancer cells.

The role of autophagy in the death of L1210 leukemia cells initiated by the new antitumor agents, XK469 and SH80.

The phenoxypropionic acid derivative 2-{4-[(7-chloro-2-quinoxalinyl)oxy]phenoxy}propionic acid (XK469) and an analogue termed 2-{4-[(7-bromo-2-quinalinyl)oxy]phenoxy}propionic acid (SH80) can eradicate malignant cell types resistant to many common antitumor agents. Colony formation assays indicated that a 24 h exposure of L1210 cells to XK469 or SH80 inhibited clonogenic growth with CI(90) values of 10 and 13 micromol/L, respectively. This effect was associated with G(2)-M arrest and the absence of any detectable markers of apoptosis (i.

Synthesis and biological evaluation of conformationally constrained analogs of the antitumor agents XK469 and SH80. Part 5.

Conformational restriction of bioactive molecules offers the possibility of generating structures of increased potency. To this end, a synthesis has been achieved of (R,S)-2-[(8-chlorobenzofurano[2,3-b]quinolinyl)oxy]propionic acid (12a), a highly rigidified, polycyclic analog of 2-[4-[(7-chloro-2-quinoxalinyl)oxy]phenoxy]propionic acid (2a, XK469). Efforts to effect the same synthesis of the corresponding 8-bromo-derivative led to a mixture of intermediate, 8-chloro (9a), and 8-bromo-2-hydroxybenzofurano[2,3-b]quinoline (9b), generated by halogen-exchange, via an aromatic S(RN)1(A(RN)1) reaction of precursor, 8b, with pyridine hydrochloride.

Synthetic modification of the 2-oxypropionic acid moiety in 2-{4-[(7-chloro-2-quinoxalinyl)oxy]phenoxy}propionic acid (XK469), and consequent antitumor effects. Part 4.

The criteria for the activity of 2-{4-[(7-chloro-2-quinoxalinyl)oxy]phenoxy}propionic acid (XK469) and 2-{4-[(7-bromo-2-quinolinyl)oxy]phenoxy}propionic acid (SH80) against transplanted tumors in mice established in previous studies, require a (7-halo-2-quinoxalinoxy)- or a (7-halo-2-quinolinoxyl)-residue, respectively, bridged via a 1,4-OC(6)H(4)O-linker to C(2) of propionic acid. The present work demonstrates that substitution of fluorine at the 3-position of the 1,4-OC(6)H(4)O-linker of XK469 leads to a 10-fold reduction in activity, whereas the corresponding 2-fluoro analog proved to be 100-fold less active than XK469. Moreover, the latter tolerated substitution of but a single, additional methyl group to the 2-position of the propionic acid moiety, that is, the isobutyric acid analog, without loss of significant in vivo activity.

Part 3: synthesis and biological evaluation of some analogs of the antitumor agents, 2-{4-[(7-chloro-2-quinoxalinyl)oxy]phenoxy}propionic acid, and 2-{4-[(7-bromo-2-quinolinyl)oxy]phenoxy}propionic acid.

2-{4-[(7-Chloro-2-quinoxalinyl)oxy]phenoxy}propionic acid (X469) and 2-{4-[(7-bromo-2-quinolinyl)oxy]phenoxy}propionic Acid (SH80) are among the most highly and broadly active antitumor agents to have been developed in our laboratories. However, the mechanism(s) of action of these agents remain to be elucidated, which prompted our continued endeavor to delineate a pharmacophoric pattern, from which a putative target might be deduced. Herein, we provide additional evidence that intact quinoxaline and quinoline rings in XK469 and SH80, respectively, are fundamental to the activities of these structures against transplanted tumors in mice.

II. Synthesis and biological evaluation of some bioisosteres and congeners of the antitumor agent, 2-(4-[(7-chloro-2-quinoxalinyl)oxy]phenoxy)propionic acid (XK469).

XK469 (1) is among the most highly and broadly active antitumor agents to have been evaluated in our laboratories. Subsequent developmental studies led to the entry of (R)-(+) 1 (NSC 698215) into phase 1 clinical trials (NIH UO1-CA62487). The antitumor mechanism of action of 1 remains to be elucidated, which has prompted a sustained effort to elaborate a pharmacophoric pattern of 1.

Lack of in vitro-in vivo correlation of a novel investigational anticancer agent, SH 30.

In solid tumors, the reasons for the lack of in vitro and in vivo correlation of drug activities are multifold and includes permeability to the tumor cells, interstitial hypertension and metabolic degradation. So, it is important to study the permeability and metabolic disposition of new compounds early in discovery and development of anticancer drugs. An experimental anti-cancer drug, SH 30 demonstrated highly selective and potent cytotoxic activity against a number of multi-drug resistant tumor cell lines in vitro.