There is an ever growing need for a fluxless chip join process to alleviate the difficulties associated with flux cleaning in small gaps and to target fluxless packaging applications such as required for advanced photonics. Moreover, a fluxless process can enable new process flows such as in-line underfill of fragile structures or a combination tack and mass reflow operations for 3D packages. This paper discusses the development of a continuous mass reflow chip join furnace using formic acid atmosphere for fluxless, flip chip organic packaging applications.A proposed reaction mechanism between formic acid and tin oxide will be discussed. This understanding provides the basis for the reflow furnace design and the associated experimentation. A description of the prototype mass reflow furnace is provided including the formic acid delivery and abatement systems. Experimental data includes the choice of temporary adhesive material and dispense pattern to hold the assembly in place prior to reflow for chip and capacitors as well as wettability data for different formic acid concentration profiles, temperature profiles and soak times. Several test vehicles were used to investigate the impact of bump metallurgy, die size and gap between the die and organic substrate on the effectiveness of formic acid to reduce tin oxide. The impact of oxygen level was found to be critical for wettability and temporary adhesive behavior - data to support very low oxygen level is presented. A cleanliness assessment was performed on samples after chip removal and includes visual inspection, SEM and EDS data as well as XPS surface study with focus on tin redeposition. Reliability data for DTC testing of modules is presented as well as cross-sections of the interconnections formed under formic acid atmosphere.

In this work, we investigated the flip chip lead-free solder joint cracking phenomenon. A study on the occurrence and severity of solder joint cracking before the encapsulation operation across several device technologies enabled the identification of the dominant parameters. The respective influence of CJ reflow profile, solder joint density in chip corners, substrate core thickness and the solder voiding are discussed with respect to this phenomenon. The CJ reflow profile was found to be the most significant parameter in this study. The influence of the CJ reflow profile is described with respect to measured chip warpage reduction and frequency of solder joint cracking. Amongst the more secondary relationships, a comparison between various solder joint densities in chip corners revealed that higher solder joint density exhibits an improved resistance to crack occurrence and propagation. In terms of substrate core thickness, coreless packages have shown to be more sensitive than packages with cored substrates to mechanical stresses and vibrations that can induce cracking. Finally, the presence of voids in solder was found to be an aggravating parameter based predominantly on its effect on cracking severity. These relationships are discussed in detail along with hypotheses to support same.

The design, synthesis, and biological evaluation of N-(2-aminophenyl)-4-[(4-pyridin-3-ylpyrimidin-2-ylamino)methyl]benzamide 8 (MGCD0103) is described. Compound 8 is an isotype-selective small molecule histone deacetylase (HDAC) inhibitor that selectively inhibits HDACs 1-3 and 11 at submicromolar concentrations in vitro. 8 blocks cancer cell proliferation and induces histone acetylation, p21 (cip/waf1) protein expression, cell-cycle arrest, and apoptosis. 8 is orally bioavailable, has significant antitumor activity in vivo, has entered clinical trials, and shows promise as an anticancer drug.

Inhibition of histone deacetylases (HDAC) is emerging as a new strategy in human cancer therapy. The synthesis and biological evaluation of a variety of 4-(heteroarylaminomethyl)-N-(2-aminophenyl)-benzamides is presented herein. From the different series bearing a six-membered heteroaromatic ring studied, the s-triazine series showed the best HDAC1 enzyme and in vitro anti-proliferative activities with IC(50) values below micromolar range. Some of these compounds can also significantly reduce tumor growth in human tumor xenograft models in mice.

Analogues of the clinical compound MGCD0103 (A) were designed and synthesized. These compounds inhibit recombinant human HDAC1 with IC(50) values in the sub-micromolar range. In human cancer cells growing in culture these compounds induce hyperacetylation of histones, cause expression of the tumor suppressor protein p21(WAF1/CIP1), and inhibit cellular proliferation. Lead molecule of the series, compound 25 is metabolically stable, possesses favorable pharmacokinetic characteristics and is orally active in vivo in different mouse tumor xenograft models.

A variety of N-(2-amino-phenyl)-4-(heteroarylmethyl)-benzamides were designed and synthesized. These compounds were shown to inhibit recombinant human HDAC1 with IC(50) values in the sub-micromolar range. In human cancer cells growing in culture these compounds induced hyperacetylation of histones, induced the expression of the tumor suppressor protein p21(WAF1/Cip1), and inhibited cellular proliferation. Certain compounds of this class also showed in vivo activity in various human tumor xenograft models in mice.

Significant effort is being made to understand the role of HDAC isotypes in human cancer and to develop antitumor agents with better therapeutic windows. A part of this endeavor was the exploration of the 14 A internal cavity adjacent to the enzyme catalytic site, which led to the design and synthesis of compound 4 with the unusual bis(aryl)-type pharmacophore. SAR studies around this lead resulted in optimization to potent, selective, nonhydroxamic acid HDAC inhibitors.

The synthesis and biological evaluation of a variety of 4-(heteroarylaminomethyl)-N-(2-aminophenyl)-benzamides and their analogs is described. Some of these compounds were shown to inhibit HDAC1 with IC(50) values below the micromolar range, induce hyperacetylation of histones, upregulate expression of the tumor suppressor p21(WAF1/Cip1), and inhibit proliferation of human cancer cells. In addition, certain compounds of this class were active in several human tumor xenograft models in vivo.

4725 Targeting histone deacetylases (HDACs) is a new approach in human cancer therapy in recent years. Currently several HDAC pan-inhibitors are in clinical trials, such as SAHA. We hypothesized that isotype-specific HDAC inhibitors will exhibit significant antitumor activity but have less side effects as human cancer therapeutic agents. As our initial effort, we designed and synthesized the isotype-selective HDAC inhibitor MGCD0103 which targets to HDAC1, 2, 3 and 11 and in vitro and exhibits significant antitumor activity in vivo . In order to further understand the isotype-specific role of HDAC enzymes, especially class I HDAC enzymes, in human cancers, we designed a class of thiophenyl substituted benzamides as novel HDAC inhibitors. In this poster, as a typical example of compounds resulting from this approach, we describe the biological assessment of the thiophenyl derivative of CI-994 (Compound 1) both in vitro and in vivo . We demonstrate that thiophenyl modification of CI-994 significantly enhanced HDAC inhibitory activity against its target HDAC enzymes and changes its selectivity profiles both in vitro and in cancer cells. Consistent with its enzyme inhibitory potency in vitro , antiproliferative activity of Compound 1 is much more potent than its parental CI-994 in various cancer cell lines in vitro . Compound 1 also exhibits antitumor activity in xenograft models in mice in vivo . Selective inhibition of HDAC enzymes by thiophenyl-substituted benzamides may be a novel approach to identify anti-cancer agents.

Inhibition of histone deacetylases (HDACs) is emerging as a new strategy in human cancer therapy. Novel 2-aminophenyl benzamides and acrylamides, that can inhibit human HDAC enzymes and induce hyperacetylation of histones in human cancer cells, have been designed and synthesized. These compounds selectively inhibit proliferation and cause cell cycle arrest in various human cancer cells but not in normal cells. The growth inhibition of 2-aminophenyl benzamides and acrylamides against human cancer cells in vitro is reversible and is dependent on the induction of histone acetylation. Compounds of this class can significantly reduce tumor growth in human tumor xenograft models.

Histone deacetylases (HDACs) and histone acetyltransferases (HATs) are enzymes that catalyze the deacetylation and acetylation of lysine residues located in the NH(2) terminal tails of histones and non-histone proteins. Perturbation of this balance is often observed in human cancers and inhibition of HDACs has emerged as a novel therapeutic strategy against cancer. To date, more that 30 groups, academic and industrial, are involved in research related to these target enzymes. Over the past year, dozens of research papers and patent applications describing new HDAC inhibitors belonging to different structural classes have been disclosed. The present review highlights the latest developments in design and synthesis of HDAC inhibitors -- potential anti-cancer drugs.