Kenneth F. Bastow

Antitumor agents. Part 214: synthesis and evaluation of curcumin analogues as cytotoxic agents.

Fifty-eight curcumin analogues were prepared and evaluated for in vitro cytotoxicity against a panel of human tumor cell lines. Compound was the most potent analogue against several cell lines, including HOS (bone cancer) and 1A9 (breast cancer), with ED50 values of 0.97 and <0.63 microg/mL, respectively.

Antitumor agents 201.1 Cytotoxicity of harmine and β-carboline analogs

Twenty-six beta-carbolines were evaluated for in vitro cytotoxicity in a human tumor cell line panel. Harmine (3) showed significant activity against several cell lines including three drug-resistant KB sublines with various resistance mechanisms. Alpha-(4-nitrobenzylidine) harmine (16) had a broad cytotoxicity spectrum (ED50 values from 0.3-1.2 microg/mL against 1A9, KB, SaOS-2, A549, SK-MEL-2, U-87-MG, and MCF-7 cells).

Simple isoquinoline and benzylisoquinoline alkaloids as potential antimicrobial, antimalarial, cytotoxic, and anti-HIV agents

Twenty-six simple isoquinolines and 21 benzylisoquinolines were tested for antimicrobial, antimalarial, cytotoxic, and anti-HIV activities. Some simple isoquinoline alkaloids were significantly active in each assay, and may be useful as lead compounds for developing potential chemotherapeutic agents. These compounds include 13 (antimicrobial), 25, 26, and 42 (antimalarial), 13 and 25 (cytotoxic), and 28 and 29 (anti-HIV). A quaternary nitrogen atom of isoquinolium or dihydroisoquinolinium type may contribute to enhanced potency in the first three types of activities. In contrast, anti-HIV activity was found with tetrahydroisoquinoline and 6,7-dihydroxyisoquinolium salts.

Antitumor agents 200. Cytotoxicity of naturally occurring resveratrol oligomers and their acetate derivatives.

Eleven resveratrol oligomers and six acetylated derivatives were evaluated for in vitro cytotoxicity against a panel of human tumor cell lines. The acetate of (-)-ampelopsin A (12) showed potent and selective cytotoxic activity with ED50 values of 0.6, 0.7 and 2.0 microg/mL against KB, 1A9 and MCF-7 cells, respectively. Hopeaphenol (10) and pallidol hexaacetate (13) also showed significant cytotoxicity against KB cells with ED50 values of 1.2 and 1.6 microg/mL, respectively.

Novel mechanisms of DNA topoisomerase II inhibition by pyranonaphthoquinone derivatives—eleutherin, α lapachone, and β lapachone∗

Abstract Pyranonaphthoquinones have diverse biological activities against Gram-positive bacteria, fungi, and mycoplasms, and, recently, there has also been an increasing interest in their anti-cancer activity. This study includes three derivatives: eleutherin (compound 1), β lapachone (compound 2), and its structural isomer, α lapachone (compound 3). The mechanism of topoisomerase II inhibition by the three derivatives was examined systematically with respect to the steps of the catalytic cycle of the enzyme. Etoposide, the prototypical enzyme poison, was used as a control and in combination with compounds 1–3 to localize their mechanism of action. The study revealed that eleutherin (1) and β lapachone (2) inhibited topoisomerase II by inducing religation and dissociation of the enzyme from DNA in the presence of ATP. Whereas compound 2 was an “irreversible” inhibitor of topoisomerase II, compound 1 merely slowed the catalytic cycle of the enzyme. α Lapachone (3), on the other hand, inhibited initial non-covalent binding of topoisomerase II to DNA and, in addition, induced religation of DNA breaks (even in pre-established ternary complexes) before dissociating the enzyme from DNA. Compound 3 was an “irreversible” inhibitor of topoisomerase II. The diverse and unique mechanisms of topoisomerase II inhibition by pyranonaphthoquinone derivatives reveal novel ways to target the enzyme with potential for anti-cancer drug design.

Anti-HBV and cytotoxic activities of pyranocoumarin derivatives.

Four natural pyranocoumarins clausenidin (1), nordentatin (2), clausarin (3), and xanthoxyletin (4) were isolated from the medicinal plant Clausena excavata. Recently, we found that 1 and 2 suppressed hepatitis B virus surface antigen in HepA2 cells, and in addition, 1-3 showed cytotoxic activity against four human cancer cell lines (A549, MCF7, KB, and KB-VIN). To explore the SAR of 1-4, 17 pyranocoumarin analogues (5-21) were designed and synthesized. Among these analogues, 5 and 10 were the most potent against hepatitis B virus with EC(50) values of 1.14 and 1.34microM, respectively. The most interesting result in the cytotoxicity assay was the significant activity of 1, 5, and 6 against the multi-drug resistant cell line, KB-VIN, without activity against the KB cell line. These data suggest that these three compounds could be useful hits for developing MDR-inverse drugs.

A Novel Bridged Stilbenoid Trimer and Four Highly Condensed Stilbenoid Oligomers in Vatica rassak.

Abstract Vaticanol G ( 1 ) and vaticaside D ( 2 ) isolated from stem bark of Vatica rassak (Dipterocarpaceae) were the first instance of stilbenoid trimers with an unusual tribenzobicyclo[3.3.2]decatriene system. Vaticanols D ( 3 ) and H ( 4 )–J ( 6 ) were elucidated to be a stilbenoid hexamer or heptamer containing a structurally identical trimeric unit. Their structures and the relative configurations were established on the basis of 2D NMR spectroscopy. The hexamers ( 3 , 4 and 5 ) and the heptemer ( 6 ) showed cytotoxicity against KB cells.

Design, synthesis, and biological evaluation of Mannich bases of heterocyclic chalcone analogs as cytotoxic agents

The chalcone skeleton (1,3-diphenyl-2-propen-1-one) is a unique template that is associated with various biological activities. We synthesized Mannich bases of heterocyclic chalcones (9-47) using a one-step Claisen-Schmidt condensation of heterocyclic aldehydes with Mannich bases of acetophenones, and tested the target compounds for cytotoxicity against three human cancer cell lines (prostate, PC-3; breast, MCF-7; nasopharynx, KB) and a multi-drug resistant subline (KB-VIN). Out of the 39 chalcones synthesized, 31 compounds showed potent activity against at least one cell line with IC(50) values ranging from 0.03 to 3.80 microg/mL. Structure-activity relationships (SAR) are also discussed.

Antitumor Agents. 266. Design, Synthesis, and Biological Evaluation of Novel 2-(Furan-2-yl)naphthalen-1-ol Derivatives as Potent and Selective Antibreast Cancer Agents

In a continuing study, we explored how the individual rings in neo-tanshinlactone (1) influence its potent and selective in vitro antibreast cancer activity. Accordingly, we discovered a novel class of antibreast cancer agents, 2-(furan-2-yl)naphthalen-1-ol derivatives, based on an active C-ring opened model compound 5. Further optimization led to 18 and 21, which showed decreased cytotoxic potency but better selectivity than neo-tanshinlactone analogue 2. Interestingly, 20 showed broad cytotoxicity against human cancer cell lines.

Antitumor agents. 272. Structure-activity relationships and in vivo selective anti-breast cancer activity of novel neo-tanshinlactone analogues.

Neo-tanshinlactone (1) and its previously reported analogues, such as 2, are potent and selective in vitro antibreast cancer agents. The synthetic pathway to 2 was optimized from seven to five steps, with a better overall yield. Structure-activity relationships studies on these compounds revealed some key molecular determinants for this family of antibreast agents. Several derivatives (19-21 and 24) exerted potent and selective antibreast cancer activity with IC(50) values of 0.3, 0.2, 0.1, and 0.1 microg/mL, respectively, against the ZR-75-1 cell lines. Compound 24 was 2- to 3-fold more potent than 1 against SK-BR-3 and ZR-75-1. Importantly, 21 exhibited high selectivity; it was 23 times more active against ZR-75-1 than MCF-7. Compound 20 had an approximately 12-fold ratio of SK-BR-3/MCF-7 selectivity. In addition, analogue 2 showed potent activity against a ZR-75-1 xenograft model, but not PC-3 and MDA-MB-231 xenografts, as well as high selectivity against breast cancer cell line compared with normal breast tissue-derived cell lines. Further development of lead compounds 19-21 and 24 as clinical trial candidates is warranted.