Discovery of Small Molecule Integrin α_vβ₃ Antagonists as Novel Anticancer Agents

Abstract

Integrin alphavbeta3 has been implicated in multiple aspects of tumor progression and metastasis. Many tumors have high expression of alphavbeta3 that correlates with tumor progression. Therefore, alphavbeta3 receptor is an excellent target for drug design and delivery. We have discovered a series of novel alphavbeta3 antagonists utilizing common feature pharmacophore models. Upon validation using a database of known alphavbeta3 receptor antagonists, a highly discriminative pharmacophore model was used as a 3D query. A search of a database of 600 000 compounds using the pharmacophore Hypo5 yielded 832 compounds. On the basis of structural novelty, 29 compounds were tested in alphavbeta3 receptor specific binding assay and four compounds showed excellent binding affinity. A limited SAR analysis on the active compound 26 resulted in the discovery of two compounds with nanomolar to subnanomolar binding affinity. These small-molecule compounds could be conjugated to paclitaxel for selective delivery to alphavbeta3 positive metastatic cancer cells.

Synthesis, in vitro anticancer and antioxidant activity of thiadiazole substituted thiazolidin-4-ones

“…Thiazolidin-4-one derivatives have been reported for broad spectrum of biological activities such as antioxidant (2), anticancer (3,4), anti-inflammatory (5, 6), antimicrobial (7,8), anti-HIV (9, 10), antiviral (11), anticonvulsant (12,13), and antihypertensive (14) activities. Mechanisms of thiazolidin-4-one and related heterocycles for anticancer activity may be associated with their affinity to anticancer biotargets, such as non-membrane protein tyrosine phosphatase (SHP-2) (15), JNK-stimulating phosphatase-1 (JSP-1) (16) tumor necrosis factor TNF-a (17), antiapoptotic biocomplex Bcl-X L -BH3 (18) and integrin a v b 3 (19), etc. On the other hand, azoles are proven chemotherapeutic agents.…”

Emergence of Small-Molecule Non-RGD-Mimetic Inhibitors for RGD Integrins

“…The authors later confirmed this hypothesis using a series of analogues in which this distance was varied. 62 This study showed that shortening the compound by one carbon (compound 15) caused a greater than 100-fold decrease in potency, and lengthening by one carbon (compound 16) was also unfavorable, resulting in micromolar inhibition, Figure 9. …”

A facile, metal-free, oxidative coupling of new 6-(hetero)aryl-[1,2,5]-oxadiazolo[3,4-b]pyrazines with pyrroles, indoles and carbazoles

“…The optimal conditions, found for the reaction of 5-phenyl- [1,2,5]oxadiazolo [3,4-b]pyrazine (1a) with pyrroles, indoles and carbazoles, have been applied for the C-C coupling of 5-(hetero)aryl- [1,2,5]oxadiazolo [3,4-b]pyrazines (1b-d) with the same nucleophiles. Highly electrophilic azines (1a-d) have been found to react smoothly with pyrroles (7,8), indoles (11)(12)(13) and carbazoles (17)(18)(19) at room temperature to give the corresponding products 9-10, 14-16 and 20-22 in 71% , 87% and 76% yields, respectively. It is worth noting that structures of the SN Hproducts 9a, 10d, 14a, 21a, 22a and 22c have been established unequivocally by X-ray crystallography (Figs.…”

“…10 Also, the addition of ferrocenyl lithium or cymantryl lithium at C(6) of furazano [3,4-b]pyrazines 1, followed by oxidation of the intermediate σ H -adducts, affords the corresponding metallocene derivatives 4 and 5 (Scheme 1). 11 Finally, 6-styryl-5-(hetero)aryl-furazano [3,4- [3,4-b]pyrazines.…”