Three top Syrian military officials have been killed in a suicide bomb attack in Damascus, including Syria's defence minister, former defence minister and President Bashar al-Assad's brother-in-law.

The Wednesday's attack is the harshest blow to the Syrian government since the uprising began 16 months ago.

Syrian state TV says the blast happened during a meeting of Cabinet ministers and senior security officials in Damascus. The capital has seen four days of clashes between rebels and government troops.

65 years old Defence Minister Dawoud Rajiha is the most senior government official to have been killed. Deputy Defence Minister, General Assef Shawkat, who was married to Assad's elder sister, was also killed. Hassan Turkomani, a former defence minister and senior military official died from wounds sustained in the blast.

Syrian television says Interior Minister Mohammed Shaar has also been wounded but is in a stable condition.

Syrian state television has reported that a suicide "terrorist explosion" has struck a national security building in Damascus, killing the defence minister, General Dawoud Rajha.

Omran Zoabi, Syrian Information Minister, says, "Our thoughts are with the families of our Defence Minster, the Deputy Defence Minister and former Defence Minister."

A member of the Turkey-based opposition Syrian National Council says the latest bombing in Damascus sends a clear message to the Syrian government that no one is safe.

Omar Shawaf, Syrian National Council, says, "This sends a message to the Syrian regime that the Syrian people and the Free Syrian Army can reach anyone inside Damascus and even Bashar Assad is not safe anymore. And it sends a message to the international community that the threat of sanctions has no effect."

Syria has appointed Fahad Jassim al-Freij as new Defence Minister, previously the Armed Forces' Chief of Staff.

Fahad Jassim Al-freij, new Defense Minister, says, "The Defence Minster and General Assef Shawkat, his Deputy Minister, were killed by a criminal terrorist attack on the meeting of minsters in Damascus.

We regard those who have died for this country and its dignity, as martyrs. This terrorist attack will not deter our armed forces from carrying out their duty and finding the perpetrators who threaten the security of this nation and its civilians."

The assassinations signal a turning point in the civil war as the violence becomes increasingly chaotic.